Nitrocatechol derivatives as COMT inhibitors

ABSTRACT

New compounds of formula I are described. The compounds have potentially valuable pharmaceutical properties in the treatment of some central and peripheral nervous system disorders.

This application is a continuation of U.S. application Ser. No.13/442,356, filed Apr. 9, 2012 and now U.S. Pat. No. 8,907,099, which isa continuation of U.S. application Ser. No. 11/989,447, filed Jan. 24,2008 and now U.S. Pat. No. 8,168,793, which, in turn, is the U.S.National Stage of International Application No. PCT/PT2006/000020, filedJul. 26, 2006, published in English, and claims priority under 35 U.S.C.§119 or 365 to European Application No. 06011073.1, filed May 30, 2006;European Application No. 06008203.9, filed Apr. 20, 2006; and UnitedKingdom Application No. 0515327.5, filed Jul. 26, 2005. The entirecontents of each of the aforementioned applications are incorporatedherein by reference.

This invention relates to novel substituted nitrocatechols, their use inthe treatment of some central and peripheral nervous system disordersand pharmaceutical compositions containing them.

Despite being used in clinical practice for several decades, levodopa(L-DOPA) continues to be the gold standard drug for the symptomatictreatment of Parkinson's disease. This has helped to maintain keeninterest in the development of inhibitors of the enzymecatechol-O-methyltransferase (COMT) based on the hypothesis thatinhibition of this enzyme may provide clinical improvements in patientsafflicted by Parkinson's disease undergoing treatment with L-DOPA and aperipheral amino acid decarboxylase (AADC) inhibitor. The rationale forthe use of COMT inhibitors as adjuncts to L-DOPA/AADC therapy is basedon their ability to reduce metabolic O-methylation of L-DOPA to3-O-methyl-L-DOPA (3-OMD). The duration of L-DOPA induced clinicalimprovement is brief as a result of the short in vivo half-life ofL-DOPA which contrasts with the long half-life of 3-OMD. Additionally,3-OMD competes with L-DOPA for transport across the blood-brain barrier(BBB), which means that only a very limited amount of an orallyadministered dose of L-DOPA actually reaches the site of action, i.e.the brain. Commonly, within only a few years of starting L-DOPA therapywith the usual dosage regime, L-DOPA induced clinical improvementdeclines at the end of each dose cycle, giving rise to the so-called‘wearing-off’ pattern of motor fluctuations. A close relationshipbetween the ‘wearing-off’ phenomenon and accumulation of 3-OMD has beendescribed (Tohgi, H., et al., Neurosci. Letters, 132:19-22, 1992). Ithas been speculated that this may result from impaired brain penetrationof L-DOPA due to competition for the transport system across the BBBwith 3-OMD (Reches, A. et al., Neurology, 32:887-888, 1982) or moresimply that there is less L-DOPA available to reach the brain (Nutt, J.G., Fellman, Clin. Neuropharmacol., 7:35-49, 1984). In effect, COMTinhibition protects L-DOPA from metabolic breakdown in the peripherythrough O-methylation, such that with repeated doses of L-DOPA, the meanplasma L-DOPA concentration is raised. In addition to reducedcompetition for transport into the brain, a significantly greaterpercentage of the orally administered dose of L-DOPA is able to reachthe site of action. Thus COMT inhibition serves to increase thebioavailability of L-DOPA and the duration of antiparkinsonian action isprolonged with single doses of L-DOPA (Nutt, J. G., Lancet,351:1221-1222, 1998).

The most potent COMT inhibitors thus far reported are3,4-dihydroxy-4′-methyl-5-nitrobenzophenone (Tolcapone, Australian pat.AU-B-6976487),(E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide(Entacapone, German pat. DE 3740383 A1) and BIA 3-202 (U.S. Pat. No.6,512,136) which all have inhibition constants in the low nanomolarrange. Although sharing essentially the same pharmacophore, tolcaponediffers from entacapone and BIA 3-202 in that it easily enters thecentral nervous systems (CNS) and is able to inhibit cerebral COMT aswell as peripheral COMT. It could be speculated that central inhibitionmay be less important if the more significant action of inhibiting COMTis to prevent breakdown of L-DOPA in the periphery. Indeed, the use ofCOMT inhibitors which do not penetrate into the brain at clinicallyrelevant doses may avoid potential undesired CNS side-effects of theseagents.

Another serious issue which has emerged since these COMT inhibitors wereintroduced into clinical practice relates to the potential of thesenitrocatechol-based xenobiotics to cause severe liver damage(hepatotoxicity). Indeed, shortly after its launch, tolcapone waswithdrawn from the market after several cases of hepatotoxicity werereported including three unfortunate deaths from fatal fulminanthepatitis. Today tolcapone can only be used in Parkinsonian patients whoare unresponsive to other treatments and strictly only with regularmonitoring of liver function, which is expensive and inconvenient forthe patient. Although the actual mechanistic causes of the livertoxicity associated with tolcapone are not fully understood, in vitrostudies have shown that tolcapone may be reduced metabolically toreactive intermediates and it has been speculated that these may formcovalent adducts with hepatic proteins resulting in hepatocellularinjury (Smith, K. S. et al, Chem. Res. Toxicol., 16:123-128, 2003).

Entacapone on the other hand, although sharing the same nitrocatecholpharmacophore with tolcapone, is not associated with liver toxicity andis generally regarded as a safe drug. Unfortunately however, entacaponeis a significantly less potent COMT inhibitor than tolcapone and has amuch shorter in-vivo half-life. This means that entacapone has a verylimited duration of effect and as a consequence, the drug must beadministered in very high doses with every dose of L-DOPA taken by thepatient. As such, the clinical efficacy of entacapone has beenquestioned—indeed a recent study (Parashos, S. A. et al., Clin.Neuropharmacol., 27(3): 119-123, 2004) revealed that the principalreason for discontinuation of entacapone treatment in Parkinson'sdisease patients was a perceived lack of efficacy.

In summary, there still remains a clear clinical requirement for a safeand effective COMT inhibitor for adjunctive therapy in the management ofthe symptoms of Parkinson's disease. Preferably, the COMT inhibitorshould be endowed with greater potency and duration of COMT inhibitionthan entacapone, which would lead to greater clinical efficacy. Morepreferably, the COMT inhibitor should, unlike tolcapone, have limitedaccess to the CNS, i.e. it should preferentially inhibit peripheral COMTrather than central COMT. Even more preferably, the COMT inhibitorshould combine the aforementioned features and in addition should not beendowed with potential to cause liver toxicity as seen with tolcapone.

We have now surprisingly found that certain nitrocatechols are verypotent COMT inhibitors which are also devoid of, or have greatlyreduced, toxicity risk. Furthermore, it has been unexpectedlyascertained that it is the chemical functionality of the non-catecholicsubstituent connected to the heterocyclic ring that determines the lackof toxic effects of the compounds.

To date, there has been only one reported example of a nitrocatecholic[1,2,4]-oxadiazole in the prior art (Example 75 of Australian pat.AU-B-6976487), this being5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-nitropyrocatechol 1, which has thechemical structure shown below;

This substance is a 3,5-disubstituted-[1,2,4]-oxadiazole with the methylgroup occupying position C-3 of the heterocyclic oxadiazolyl ring andthe nitrocatecholic pharmacophore attached to C-5.

We have studied the oxadiazolyl compound 1 mentioned above and found itto be moderately active in the COMT inhibition assay (59% of control,see experimental section). Unfortunately however, compound 1 presents asignificant toxicity risk (55% cell viability, see experimentalsection). As such, this particular compound 1 cannot be considered torepresent an adequate solution to the present problem of a providing apotent and clinically safe COMT inhibitor.

We have surprisingly found that if the central ring is substituted witha pyridyl ring in oxidised form (i.e. pyridine N-oxide), that theresulting pyridine N-oxide compounds exhibit greatly reduced toxicity,or are even devoid of toxicity risk, whilst it is still concomittantlypossible to maintain COMT inhibition superior to entacapone. If theposition of the nitrocatechol pharmacophore is ‘switched’ from C-5 tothe C-3 position of the oxadiazole ring, then the resulting compoundsare usually less active in terms of COMT inhibition. The regioisomeric1,3,4-oxadiazoles, wherein the nitrocatechol pharmacophore is attachedto C-2 of the oxadiazolyl central ring are also usually less active interms of COMT inhibition. For example, consider the regioisomers 2 and 3of the prior art oxadiazole 1 which we have also synthesised andevaluated in vivo;

Although both 2 and 3 each present a reduced toxicity risk in relationto 1, in terms of COMT inhibition compound 2 displayed only 79% ofcontrol and compound 3 was only marginally better at 64%. Thus it can beconcluded that it is the combination of the correct positionalarrangement of the heteroatoms in the central oxadiazole ring and theincorporation of the pyridine N-oxide functionality is unexpectedlycrucial for obtaining synergy between high COMT inhibitory activity andsafety for this type of COMT-inhibitor.

Accordingly, the present invention relates to nitrocatecholic COMTinhibitors which are devoid of, or have greatly reduced, toxicity risk.Furthermore, it has been unexpectedly ascertained that it is theintroduction of a nitrogen-based heterocyclic group in N-oxidised form,such as, for example, a pyridine N-oxide, that determines the lack oftoxic effects of the nitrocatecholic compounds. We have furthersurprisingly found that compounds of general formula I are COMTinhibitors which are endowed with balanced properties of bioactivity,bioavailability and, in particular, safety:

-   -   wherein R₁ and R₂ are independently from each other hydrogen or        a group which is hydrolysable under physiological conditions,        optionally substituted lower alkanoyl or aroyl; X represents a        methylene group; Y represents an atom of oxygen, NH, or sulphur;        n represents the number 0, 1, 2 or 3 and m represents the number        0 or 1; R₃ represents a pyridine N-oxide group according to the        formula A, B or C, which is connected as indicated by the        unmarked bond:

where R₄, R₅, R₆ and R₇ independently from each other representhydrogen, C₁-C₆-alkyl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy, C₆-C₁₂-aryloxy ora C₆-C₁₂-thioaryl group, C₁-C₆-alkanoyl or C₇-C₁₃-aroyl group, amino,C₁-C₆-alkylamino, C₁-C₆-dialkylamino, C₃-C₁₂-cycloalkylamino,C₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl,C₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano,nitro or a heteroaryl group; or two or more of residues R₄, R₅, R₆ andR₇ taken together represent aliphatic or heteroaliphatic rings oraromatic or heteroaromatic rings and wherein P represents a centralunit, which is preferably a planar unit and which is even morepreferably selected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl,1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl,1,3,5-triazin-2,4-diyl, 1,2,4-triazin-3,5-diyl, 2H-tetrazol-2,5-diyl,1,2,3-thiadiazol-4,5-diyl,1-alkyl-3-(alkoxycarbonyl)-1H-pyrrol-2,5-diyl, wherein alkyl isrepresented by methyl, ethyl, n-propyl and n-butyl and wherein alkoxy isrepresented by methoxy, ethoxy, n-propoxy and isopropoxy,1-alkyl-1H-pyrrol-2,5-diyl, wherein alkyl is represented by methyl,ethyl, n-propyl and n-butyl, thiazol-2,4-diyl, 1-H-pyrazol-1,5-diyl,pyrimidin-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl,isoxazol-3,5-diyl, furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl,wherein alkoxy is represented by methoxy, ethoxy, n-propoxy andisopropoxy, benzene-1,3-diyl and (Z)-1-cyanoethen-1,2-diyl.

In the above definition, the regioisomers of the central unit includeboth regioisomers realizable by exchange of the nitrocatechol moiety andthe —(X)_(n)—(Y)_(m)—R₃ moiety.

Preferably, C₁-C₆-alkyl residues represent methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl. Preferably,C₁-C₆-thioalkyl residues represent thiomethyl, thioethyl, thio-n-propyl,thio-isopropyl, thio-n-butyl, thio-n-pentyl and thio-n-hexyl.Preferably, C₁-C₆-alkoxy residues represent methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Preferably,C₆-C₁₂-aryloxy residues represent phenoxy or naphthoxy which mayoptionally be substituted. Preferably, C₆-C₁₂-thioaryl residuesrepresent thiophenyl and thionaphthyl which may optionally besubstituted. Preferably, C₁-C₆-alkanoyl residues represent methanoyl,ethanoyl, propanoyl or butanoyl. Preferably, C₇-C₁₃-aroyl residuesrepresent benzoyl and naphthoyl. Preferably, C₁-C₆-alkylamino residuesrepresent methylamino, ethylamino, n-propylamino, isopropylamino andn-butylamino. Preferably, C₁-C₆-dialkylamino residues representdimethylamino, diethylamino, di-n-propylamino, di-n-butylamino,di-isopropylamino, methylethylamino, methylpropylamino andethylpropylamino. Preferably, C₃-C₁₂-cycloalkylamino residues representpyrrolidino, piperidino, cyclohexylamino and dicyclohexylamino.Preferably, C₃-C₁₂-heterocycloalkylamino residues represent morpholino,2,6-dimethylmorpholino, 3,5-dimethylmorpholino, piperazino,N-methylpiperazino and N-ethylpiperazino. Preferably,C₁-C₆-alkylsulphonyl or C₆-C₁₂-arylsulphonyl residues representmethylsufonyl, ethylsulfonyl, phenylsulfonyl, and tolylsulfonyl.Preferably, halogen residues represent chloro, bromo, iodo and fluoro.Preferably, C₁-C₆-haloalkyl represents chloromethyl, fluoromethyl,dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.Preferably, heteroaryl residues represent pyridyl, pyrimidyl,isoxazolyl, oxazolyl, isoxadiazolyl, oxadiazolyl, triazolyl andtetrazolyl. In cases where two or more of residues R₄, R₅, R₆ and R₇taken together represent aliphatic or heteroaliphatic rings or aromaticor heteroaromatic rings, preferred combined residues are indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, naphthyridinyl,isoquinolyl and quinolyl.

Preferably, the central unit is selected from a heteroaromaticfive-membered ring which includes 1 to 4 of the heteroatoms N, O and S.More preferably, the central unit P is selected from the regioisomers of1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl,4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazin-2,4-diyl,1,2,4-triazin-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl,1-alkyl-3-(alkoxycarbonyl)-1H-pyrrol-2,5-diyl, wherein alkyl isrepresented by methyl, ethyl, n-propyl and n-butyl and wherein alkoxy isrepresented by methoxy, ethoxy, n-propoxy and isopropoxy,1-alkyl-1H-pyrrol-2,5-diyl, wherein alkyl is represented by methyl,ethyl, n-propyl and n-butyl, thiazol-2,4-diyl, 1-H-pyrazol-1,5-diyl,oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl,furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl, wherein alkoxy isrepresented by methoxy, ethoxy, n-propoxy and isopropoxy.

Most preferably, the central unit P is selected from1,3,4-oxadiazol-2,5-diyl and 1,2,4-oxadiazol-3,5-diyl.

Preferred compounds of the above general formula (I) having a1,2,4-oxadiazol-3,5-diyl as central unit include5-[3-(3,5-dichloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-chloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-morpholin-4-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,3-nitro-5-[3-(1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,5-[3-(4-bromo-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-chloro-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-morpholin-4-yl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,3-nitro-5-[3-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,5-[3-(2-methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(6-methyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2,6-dimethyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-methyl-1-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(6-methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-bromo-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-bromo-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,5-[3-(2-chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,and3-nitro-5-[3-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)pyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,5,6-trimethylpyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-fluoropyridine1-oxide,4-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-fluoropyridine1-oxide,2-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-fluoropyridine1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methylpyridine1-oxide,2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methylpyridine1-oxide, and2-bromo-5-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having a1,3,4-oxadiazol-2,5-diyl as central unit include3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,5,6-trimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-fluoropyridine1-oxide,4-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-fluoropyridine1-oxide,2-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-fluoropyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-methylpyridine1-oxide,2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-methylpyridine1-oxide, and2-bromo-5-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having a4-methyl-4H-1,2,4-triazol-3,5-diyl as central unit include3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4,5,6-trimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-fluoropyridine1-oxide,4-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-fluoropyridine1-oxide,2-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6-fluoropyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6-methylpyridine1-oxide,2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-6-methylpyridine1-oxide and2-bromo-5-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having a1,3,5-triazin-2,4-diyl as central unit include3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine1-oxide, and3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-5-(trifluoromethyl)pyridine1-oxide.

Preferred compounds of the above general formula (I) having a1,2,4-triazin-3,5-diyl as a central unit include3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-5-(trifluoromethyl)pyridine1-oxide,4-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-fluoropyridine1-oxide and2-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-6-fluoropyridine1-oxide.

Preferred compounds of the above general formula (I) having a(Z)-1-cyanoethen-1,2-diyl moiety as central unit include(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4-(trifluoromethyl)pyridine1-oxide,(Z)-2-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,6-dimethylpyridine1-oxide,(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,(Z)-5-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-(trifluoromethyl)pyridine1-oxide,(Z)-5-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,(Z)-3,5-dichloro-4-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)pyridine1-oxide,(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,(Z)-2-bromo-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,5,6-trimethylpyridine1-oxide,(Z)-2-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,5,6-trimethylpyridine1-oxide,(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-(trifluoromethyl)pyridine1-oxide,(Z)-2,5-dichloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,6-dimethylpyridine1-oxide,(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-5-(trifluoromethyl)pyridine1-oxide,(Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-fluoropyridine1-oxide,(Z)-4-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-fluoropyridine1-oxide,(Z)-2-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-fluoropyridine1-oxide,(Z)-2-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-methylpyridine1-oxide,(Z)-2-bromo-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-methylpyridine1-oxide, and(Z)-2-bromo-5-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit a furan-2,4-diyl or a 3-alkoxycarbonylfuran-2,4-diyl moiety,wherein alkoxy is represented by methoxy, ethoxy, n-propoxy andisopropoxy, include3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-4,5,6-trimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-fluoropyridine1-oxide,4-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-fluoropyridine1-oxide,2-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-6-fluoropyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-6-methylpyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-6-methylpyridine1-oxide, and2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit a 1H-imidazol-1,5-diyl moiety include3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-fluoropyridine1-oxide,2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-6-fluoropyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-6-methylpyridine1-oxide, and2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-6-methylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit a isoxazol-3,5-diyl moiety include3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,6-dimethylpyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)pyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,5,6-trimethylpyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,6-dimethylpyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-fluoropyridine1-oxide,4-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-fluoropyridine1-oxide,2-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-fluoropyridine1-oxide,2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-methylpyridine1-oxide,2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-methylpyridine1-oxide, and 2-bromo-5-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,6-dimethylpyridine 1-oxide.

Preferred compounds of the above general formula (I) having as centralunit a carbonyl moiety include3-(3,4-dihydroxy-5-nitrobenzoyl)-4-(trifluoromethyl)pyridine 1-oxide,2-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,6-dimethylpyridine 1-oxide,3-(3,4-dihydroxy-5-nitrobenzoyl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide, 5-(3,4-dihydroxy-5-nitrobenzoyl)-2-(trifluoromethyl)pyridine1-oxide,5-(3,4-dihydroxy-5-nitrobenzoyl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(3,4-dihydroxy-5-nitrobenzoyl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide, 3,5-dichloro-4-(3,4-dihydroxy-5-nitrobenzoyl)pyridine 1-oxide,3-(3,4-dihydroxy-5-nitrobenzoyl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,5,6-trimethylpyridine1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,6-dimethylpyridine1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-5-(trifluoromethyl)pyridine1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-2-fluoropyridine 1-oxide,4-(3,4-dihydroxy-5-nitrobenzoyl)-2-fluoropyridine 1-oxide,2-(3,4-dihydroxy-5-nitrobenzoyl)-6-fluoropyridine 1-oxide,2-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-6-methylpyridine 1-oxide,2-bromo-3-(3,4-dihydroxy-5-nitrobenzoyl)-6-methylpyridine 1-oxide, and2-bromo-5-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an oxazol-2,4-diyl moiety include3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,5,6-trimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-5-(trifluoromethyl)pyridine1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-fluoropyridine1-oxide, 4-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-fluoropyridine1-oxide, 2-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-fluoropyridine 1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-methylpyridine1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-methylpyridine 1-oxide, and2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an benzene-1,3-diyl moiety include3-(3′,4′-dihydroxy-5′-nitrobiphenyl-3-yl)-4-(trifluoromethyl)pyridine1-oxide,5-(3′,4′-dihydroxy-5′-nitrobiphenyl-3-yl)-2-(trifluoromethyl)pyridine1-oxide, 3,5-dichloro-4-(3′,4′-dihydroxy-5′-nitrobiphenyl-3-yl)pyridine1-oxide,3-(3′,4′-dihydroxy-5′-nitrobiphenyl-3-yl)-2-(trifluoromethyl)pyridine1-oxide, and3-(3′,4′-dihydroxy-5′-nitrobiphenyl-3-yl)-5-(trifluoromethyl)pyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an 1-H-pyrazol-1,5-diyl moiety include3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)-4-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyridine1-oxide, and4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazol-1-yl)-2-fluoropyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an pyrimidin-2,4-diyl moiety include3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-4,5,6-trimethylpyridine 1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-4,6-dimethylpyridine1-oxide, and3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidin-2-yl)-5-(trifluoromethyl)pyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an 1H-pyrrol-2,5-diyl moiety include3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-3-(ethoxycarbonyl)-1H-pyrrol-2-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)-1-methyl-1H-pyrrol-2-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1-ethyl-3-(ethoxycarbonyl)-1H-pyrrol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,5,6-trimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,6-dimethylpyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-fluoropyridine1-oxide,4-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-fluoropyridine1-oxide,2-(5-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)-1-methyl-1H-pyrrol-2-yl)-6-fluoropyridine1-oxide,2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-6-methylpyridine1-oxide,2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-6-methylpyridine1-oxide, and2-bromo-5-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an 2H-tetrazol-2,5-diyl moiety include3-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-4-(trifluoromethyl)pyridine1-oxide,5-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)pyridine1-oxide,3-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide, and3-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-5-(trifluoromethyl)pyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an 1,2,3-thiadiazol-4,5-diyl moiety include3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2-methyl-6-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-4,5,6-trimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2-fluoropyridine1-oxide,4-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-2-fluoropyridine1-oxide,2-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-6-fluoropyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-6-methylpyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-6-methylpyridine1-oxide, and2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazol-5-yl)-4,6-dimethylpyridine1-oxide.

Preferred compounds of the above general formula (I) having as centralunit an thiazol-2,4-diyl moiety include3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4-(trifluoromethyl)pyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine-1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,5-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine1-oxide,3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,5,6-trimethylpyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,5,6-trimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide,2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,6-dimethylpyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-5-(trifluoromethyl)pyridine1-oxide,3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-fluoropyridine1-oxide,4-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-fluoropyridine1-oxide,2-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-fluoropyridine1-oxide,2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-methylpyridine1-oxide,2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-methylpyridine1-oxide, and2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,6-dimethylpyridine1-oxide.

In one embodiment, compounds of the general formula I wherein thecentral unit consists of a 1,2,4-oxadiazo-3,5-diyl-moiety can beprepared by a process wherein a compound of the general formula IIA, IIBor IIC,

wherein R₄, R₅, R₆ and R₇ are defined as in the general formula I, issubjected to a cyclisation reaction comprising condensation anddehydration with a compound of the general formula III,

wherein R₈ and R₉ independently from each other represent hydrogen orsuitable protective groups for aromatic hydroxyl groups, underconditions suitable to produce oxadiazole derivatives of formula IVA,IVB or IVC,

followed by removal of the hydroxyl protecting groups to provide thecompounds of general formula I wherein the central unit consists of a1,2,4-oxadiazo-3,5-diyl-moiety.

In another embodiment, the compounds of the general formula I whereinthe central unit consists of a 1,2,4-oxadiazo-3,5-diyl-moiety can beprepared by a process wherein a compound of the general formula VA, VBor VC,

wherein R₄, R₅, R₆ and R₇ are defined as in the general formula I, issubjected to a cyclisation reaction comprising condensation anddehydration with a compound of the general formula III under conditionssuitable to produce oxadiazole derivatives of formula VIA, VIB or VIC,

followed by oxidation of the pyridyl nitrogen atom to give a compoundaccording to formula IVA, IVB or IVC as shown above and finally, ifnecessary, the removal of the hydroxyl protecting groups to provide thecompounds of general formula I wherein the central unit consists of a1,2,4-oxadiazo-3,5-diyl-moiety.

Suitable protective groups for aromatic hydroxyl groups are well knownin the art. Examples of suitable protective groups for aromatic hydroxylgroups include methyl, ethyl, isopropyl, benzyl, 4-methoxybenzyl,methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, tetrahydropyranyl,phenacyl, allyl, trimethylsilyl, tert-butyldimethylsilyl,benzyloxycarbonyl, tert-butoxycarbonyl, ester, sulphonate, carbamate,phosphinate, acetal and ketal derivatives.

In a preferred embodiment, one of the groups R₈ and R₉ is hydrogen andthe other is methyl. In a particularly preferred embodiment, R₈represents methyl and R₉ represents hydrogen.

In an alternative preferred embodiment, the protective groups R₈ and R₉are replaced with hydrogen or a group which is hydrolysable underphysiological conditions. The protective groups R₈ and R₉ may be removedindependently from each other in separate reaction steps or they may beremoved in the same reaction step. Likewise, the insertion of a groupwhich is hydrolysable under physiological conditions may take placeeither in the same or in a subsequent reaction step.

In the present invention, conditions suitable to produce oxadiazolederivatives comprise conditions which give the oxadiazole derivative inhigh yield and purity. Preferably, the yield of the desired oxadiazolederivative is at least 70%, more preferably 75 to 99%, even morepreferably 80 to 97%, and most preferably 85 to 95%. Preferably, thepurity of the desired oxadiazole derivative is at least 90%, morepreferably at least 95%, even more preferably at least 99%, and mostpreferably at least 99.5%. Following the teaching of the presentinvention the skilled person can routinely determine the most suitablereaction conditions in order to optimize the yield and purity of theoxadiazole. Parameters to be taken into consideration by the skilledperson include, but are not limited to, reagents effecting thecondensation and dehydration agents, choice of protective groups R₈ andR₉, solvent system, reaction temperature and reaction time andsolubility of reagents.

The compound of general formula III requires activation beforecondensation with a compound of formula IIA-IIC or VA-VC. Suitablereagents for activation of the compound of formula III include1,1-carbonyldiimidazole, thionyl chloride, sulfonylchloride,N,N′-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, phosgene, PCl₃, POCl₃,PCl₅, anhydrides, trichlorotriazine and chlorodimethoxytriazine and thelike. Particularly preferable are 1,1-carbonyldiimidazole and thionylchloride. In some cases, the same reagents can be employed to effect thecyclisation step, which consists of condensation and dehydration.Alternative reagents to effect condensation and/or dehydration includepyridine and tetrabutylammonium fluoride. Preferably the dehydration canbe effected by thermal heating of the reaction mixture in conjunctionwith the aforementioned reagents.

The compound of general formula III can be activated with an excess of areagent such as thionyl chloride in a suitable solvent or without theneed for additional solvent. If preferred, the excess reagent can thenbe removed, e.g. by distillation, and replaced with a solvent andanother reagent such as pyridine to effect the condensation anddehydration steps. Preferred solvent systems for activating the compoundof general formula III, and cyclisation with compounds of generalformulas IIA-IIC or VA-VC are dipolar aprotic solvents includingdimethylformamide, dimethylsulfoxide, dimethylacetamide andN-methylpyrrolidinone. Particularly preferable are dimethylsulfoxide anddimethylacetamide.

Suitable reaction temperatures and reaction times depend on thereactivity of the utilized reagents for effecting condensation anddehydration. Preferably, the reaction temperature is in the range of 0°C. to the boiling point of the utilized solvent system, more preferablyin the range of 20 to 150° C., and most preferably in the range of 25 to120° C. Preferably, the reaction time is in the range of 30 minutes to24 hours, more preferably in the range of 1 hour to 18 hours, and mostpreferably 2 to 6 hours.

In an alternative preferred embodiment, the condensation and dehydrationreaction is carried out in the presence of an organic or inorganic base.Suitable preferred bases include triethylamine, tributylamine,2,6-lutidine, N-methylmorpholine, pyridine, imidazole, N-methylimidazoleand 4-dimethylaminopyridine. Particularly preferred bases includepyridine, N-methylimidazole and 4-dimethylaminopyridine.

In a preferred embodiment of the present invention, the condensation anddehydration are conducted in two separate reaction steps. In thisparticular embodiment, different condensation and dehydration agents andsolvent systems may be utilized to optimize yield and purity of theobtained product.

In an alternative preferred embodiment of the present invention, thecondensation and dehydration are conducted sequentially in the samevessel without isolation of the O-acylated intermediates. In thisparticular embodiment, the reagents effecting the condensation anddehydration can be the same or different but are preferably identical.

The amount of reagents effecting the condensation and dehydration arenot critical. Typical amounts of reagents effecting the condensation anddehydration include at least an amount of 1 mol, preferably 2.1 mol to 5mol, more preferably 2.2 to 4 mol, and most preferably 2.3 mol to 3 mol,per mol pyridine derivative. In cases in which the reagents effectingthe condensation and dehydration also serves as solvent or co-solvent,the excess amount may be much higher.

As mentioned above, in preferred embodiments the invention includes astep in which the nitrogen atom of the pyridyl moiety VIA, VIB or VIC isoxidized under suitable conditions to the corresponding pyridyl-N-oxidederivative IVA, IVB or IVC after the cyclisation reaction.

In the present invention, suitable oxidative conditions to produce thepyridyl-N-oxide comprise conditions which give the pyridyl-N-oxidederivative in high yield and purity. Preferably, the yield of thedesired pyridyl-N-oxide derivative is at least 90%, more preferably 92to 99%, even more preferably 94 to 98%, and most preferably 95 to 97%.Preferably, the purity of the desired pyridyl-N-oxide derivative is atleast 90%, more preferably at least 95%, even more preferably at least99%, and most preferably at least 99.5%. Following the teaching of thepresent invention the skilled person can routinely determine the mostsuitable reaction conditions in order to optimize the yield and purityof the pyridyl-N-oxide. Parameters to be taken into consideration by theskilled person include, but are not limited to, oxidizing agent, amountof oxidizing agent, choice of protective groups, solvent system,reaction temperature and reaction time and solubility of reagents.

Preferred oxidizing agents include hydrogen peroxide, MnO₂, peraceticacid, trifluoroperacetic acid, t-butylhydroperoxide,m-chloroperoxybenzoic acid, persulfuric acids, Oxone®, urea hydrogenperoxide complex and trifluoroacetic anhydride, pyridiniumchlorochromate and permanganate ions. Particularly preferred is ureahydrogen peroxide complex and trifluoroacetic anhydride.

The preferred amount of oxidizing agent is in the range of equimolaramounts to a 20-fold excess to the pyridine derivative. Preferably,amount of oxidizing agent is in the range of a 1.2-fold to 10-foldexcess, more preferably 1.5-fold to 8-fold excess and most preferably2-fold to 5-fold excess.

Preferred solvent systems for conducting the oxidation are solventswhich are inert to the oxidizing agent. Particularly preferred arehalogenated solvents, such as dichloromethane, chloroform, chlorobenzeneand carbon tetrachloride, aromatic solvents such as benzene and toluene,alkanes such as cyclohexane and hexane, and ethers such as THF,1,4-dioxane and tert-butylmethylether.

Suitable reaction temperatures and reaction times depend on thereactivity of the utilized oxidizing agent. Preferably, the reactiontemperature is in the range of 0° C. to the boiling point of theutilized solvent system, more preferably in the range of 20 to 100° C.,and most preferably in the range of 40 to 80° C. Preferably, thereaction time is in the range of 30 minutes to 24 hours, more preferablyin the range of 1 hour to 18 hours, and most preferably 2 to 6 hours.

The oxidation of the pyridyl nitrogen atom can be carried out at anystage of the process of preparation of compounds according to thegeneral formula I. Preferably, the oxidation is conducted beforeformation of the compounds of formulae IIA-IIC, or alternatively afterformation of the oxadiazole ring as in compounds of formulae VIA-VIC.

In another aspect of the invention, compounds of formula IIA, IIB or TICare prepared by reacting compounds of the general formula VITA, VIIB orVIIC,

with hydroxylamine in the presence of a chelating agent under suitablereaction conditions.

In another aspect of the invention, compounds of formula VA, VB or VCare prepared by reacting compounds of the general formula VIIIA, VIIIBor VIIIC,

with hydroxylamine in the presence of a chelating agent under suitablereaction conditions.

In the present invention, suitable reaction conditions of the abovereactions comprise conditions which give the amidoxime derivative inhigh yield and purity. Preferably, the yield of the desired amidoximederivative is at least 70%, more preferably 72 to 95%, even morepreferably 75 to 90%, and most preferably 78 to 85%. Preferably, thepurity of the desired amidoxime derivative is at least 90%, morepreferably at least 95%, even more preferably at least 96%, and mostpreferably at least 97%. Following the teaching of the present inventionthe skilled person can routinely determine the most suitable reactionconditions in order to optimize the yield and purity of the amidoxime.Parameters to be taken into consideration by the skilled person include,but are not limited to, amount of hydroxylamine, choice of catalyst,nature of substituents R₄ to R₇, solvent system, reaction temperatureand reaction time and solubility of reagents.

The preferred amount of hydroxylamine is in the range of equimolaramounts to a 50-fold excess to the pyridine derivative. Preferably, theamount of hydroxylamine is in the range of a 1.2-fold to 20-fold excess,more preferably 1.5-fold to 10-fold excess and most preferably 3-fold to5-fold excess.

Preferred chelating agents include 8-hydroxyquinoline,ortho-phenanthroline and hydrates and derivatives thereof. The preferredamount of chelating agent is in the range 0.1-10 mol %, more preferably0.5-5 mol %, more preferably 0.75-3 mol % and most preferably 1-1.5 mol%.

The solvent system is not particularly limited and includes water,alcohols such as methanol, ethanol or isopropanol, ethers such as THF or1,4-dioxane, and dipolar aprotic solvents, such as dimethylsulfoxide andthe like or mixtures of these solvents.

Preferably, the reaction temperature is in the range of 0° C. to theboiling point of the utilized solvent system, more preferably in therange of 20 to 100° C., and most preferably in the range of 40 to 80° C.Preferably, the reaction time is in the range of 30 minutes to 24 hours,more preferably in the range of 1 hour to 18 hours, and most preferably2 to 8 hours.

For the preparation of pharmaceutical compositions of general formula(I), inert pharmaceutically acceptable carriers are admixed with theactive compounds. The pharmaceutically acceptable carriers may be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules and capsules. A solid carrier can be one or moresubstances which may also act as diluents, flavouring agents,solubilizers, lubricants, suspending agents, binders or tabletdisintegrating agents; it may also be an encapsulating material.

Preferably, the pharmaceutical preparation is in unit dosage form, e.g.packaged preparation, the package containing discrete quantities ofpreparation such as packeted tablets, capsules and powders in vials orampoules.

The dosages may be varied depending on the requirement of the patient,the severity of the disease and the particular compound being employed.For convenience, the total daily dosage may be divided and administeredin portions throughout the day. Determination of the proper dosage for aparticular situation is within the skill of those in the medical art.

Materials and Methods

Assay of Mouse COMT Activity

Liver samples from 60 days old NMRI mice weighing 20-30 g(Harlan-Interfauna Ibérica, Barcelona, Spain) kept ten per cage undercontrolled environmental conditions (12 h lightdark cycle and roomtemperature 24° C.), were used in all experiments. Saline perfusedtissues, obtained from pentobarbitone (60 mgkg) anaesthetised mice, wereused in the experiments. Tissues were immediately removed andhomogenised in 5 mM phosphate buffer, pH 7.8 and stored at 80° C.

COMT activity was evaluated by the ability to methylate adrenaline tometanephrine, as previously described (Vieira-Coelho, M. A.,Soares-da-Silva, P., Brain Res, 1999, 821, 69-78). Aliquots of 0.5 ml ofliver homogenates were preincubated for 20 mM with 0.4 ml of phosphatebuffer (5 mM); thereafter, the reaction mixture was incubated for 10 minwith adrenaline (500 μM; 0.1 ml) in the presence of a saturatingconcentration of S-adenosyl-L-methionine, the methyl donor (250 μM). Theincubation medium also contained pargyline (100 μM), MgCl₂ (100 μM) andEGTA (1 mM). The preincubation and incubation were carried out at 37° C.under conditions of light protection with continuous shaking and withoutoxygenation. At the end of the incubation period the tubes weretransferred to ice and the reaction was stopped by the addition of 200μl of 2 M perchloric acid. The samples were then centrifuged (200×g, 4min, 4° C.), and 500 μl aliquots of the supernatant, filtered on 0.22 μmpore size Spin-X filter tubes (Costar) were used for the assay ofmetanephrine by high pressure liquid chromatography with electrochemicaldetection.

In experiments designed to evaluate the effects of test compounds uponliver COMT, test compounds (in 5% carboxymethylcellulose) were given bygastric tube to overnight fasted mice. Thereafter, at defined intervals,livers were removed and used to determine COMT activity as describedabove.

Assay of Rat COMT Activity

Livers from 60 day old male Wistar rats weighing 240-260 g(Harlan-Interfauna Ibérica, Barcelona, Spain), kept two per cage undercontrolled environmental conditions (12 h lightdark cycle and roomtemperature 24° C.) were used in all experiments. After decapitation,the organs were immediately removed and homogenised in 5 mM phosphatebuffer of pH 7.8. COMT activity was evaluated by the ability tomethylate adrenaline to metanephrine. Aliquots of 0.5 ml of liverhomogenates were preincubated for 20 mM with 0.4 ml of phosphate buffer(5 mM); thereafter, the reaction mixture was incubated for 5 min withepinephrine (1000 μM; 0.1 ml) in the presence of a saturatingconcentration of S-adenosyl-L-methionine (500 μM), the methyl donor; theincubation medium contained also pargyline (100 μM), MgCl₂ (100 μM) andEGTA (1 mM). The preincubation and incubation were carried out at 37° C.under conditions of light protection with continuous shaking and withoutoxygenation.

In experiments designed to evaluate the oral bioavailability of testsubstances, compounds were given by gastric tube to overnight fastedrats. Thereafter, at defined intervals, animals were killed bydecapitation and livers removed and used to determine COMT activity asdescribed above. At the end of the incubation period (5 min) the tubeswere transferred to ice and the reaction was stopped by the addition of200 μl of 2 M perchloric acid. The samples were then centrifuged (200×g,4 min, 4° C.), and 500 μl aliquots of the supernatant, filtered on 0.22μm pore size Spin-X filter tubes (Costar) were used for the assay ofmetanephrine. The assay of metanephrine was carried out by means of highpressure liquid chromatography with electrochemical detection. The lowerlimits for detection of metanephrine ranged from 350 to 500 fmol (0.5 to1.0 pmol/mg protein/h).

Levels of L-DOPA and 3-O-Methyl-L-DOPA in Plasma

Rats fasted overnight were administered orally with tolcapone,entacapone and compounds of general formula I (all at 3 mgkg) or vehicle(0.5% carboxymethylcellulose, 4 ml/kg). One, 6 or 23 h later, rats wereadministered orally with L-DOPA (12 mgkg) plus benserazide (3 mgkg) orwith vehicle (0.5% carboxymethylcellulose, 4 ml/kg). One hour later ratswere anaesthetised with sodium pentobarbitone (60 mgkg, i.p.), blood wascollected through the vena cava and the whole brain was quickly removed.Blood samples were centrifuged for 15 min at 3,000 g (4° C.) and theplasma samples were stored at −80° C. till the assay of L-DOPA and3-O-methyl-L-DOPA. All animals interventions were performed inaccordance with the European Directive number 86609, and the rules ofthe “Guide for the Care and Use of Laboratory Animals”, 7th edition,1996, Institute for Laboratory Animal Research (ILAR), Washington, D.C.

Assay of L-DOPA and Catechol Derivatives

L-DOPA and 3-O-methyl-L-DOPA in blood samples were assayed by HPLC withelectrochemical detection, as previously described (Soares-da-Silva etal., Brain Res. 2000; 863:293-297). In brief, aliquots of 20 μl wereinjected into the chromatograph. The chromatographic system consisted ofa pump (Gilson 307) and a stainless steel 5 μm ODS2 column (Biophase;Bioanalytical Systems, West Lafayette, Ind.) of 25 cm length and 4.6 mmdiameter; samples were injected by means of an automatic sample injector(Gilson 231) connected to a Gilson dilutor (Gilson 401). The mobilephase was a degassed solution of citric acid 0.1 mM; sodiumoctylsulphate 0.5 mM; sodium acetate 0.1 M; Na₂EDTA 0.17 mM;dibutylamine 1 mM and methanol (10% v/v), adjusted to pH 3.5 with PCA 2M and pumped at a rate of 1.0 ml min⁻¹. The detection was carried outelectrochemically with a glassy carbon electrode, an Ag/AgCl referenceelectrode and an amperometric detector (Gilson 142); the detector cellwas operated at 0.75 V. The current produced was monitored using theGilson Unipoint HPLC software.

Cell Toxicity

The method, which detects cell toxicity of a test substance, followsthat described by Pedrosa and Soares-da-Silva (Br. J. Pharmacol., 137, 11305-1313, 2002). Briefly, Neuro 2A mouse neuroblastoma cells wereseeded in 96-well plates in 2004 per well of culture medium for cellattachment (CMA), under a CO₂/air (5%195%) humidified atmosphere at 37°C. Controls of the test system prior to incubations consisted in amorphological control (light microscopy) of the cultured cells:attachment, spreading and density. Five days after seeding (24 h aftercells become confluent), the test compounds were incubated for 24 h withcultured cells. Cultures with no test article or ethanol were run inparallel as negative and positive controls. All incubations containedthe same percentage of solvent needed for the test compound.

Cell viability was measured using calcein-AM (Molecular Probes, Eugene,Oreg., USA). The membrane permeant calcein-AM, a nonfluorescent dye, istaken up and converted by intracellular esterases to membrane impermeantcalcein, which emits green fluorescence. After treatment with testarticle or vehicle for 24 h, cells are washed twice with Hanks' medium(medium composition, in mM: NaCl, 137; KCl, 5; MgSO₄, 0.8; Na₂HPO₄,0.33; KH₂PO₄, 0.44; CaCl₂, 0.25; MgCl₂, 1.0; Tris HCl, 0.15 and sodiumbutyrate, 1.0, pH=7.4) and loaded with 2 μM calcein-AM in Hanks' medium,at room temperature for 30 min. Fluorescence is measured at 485 nmexcitation and 530 nm emission wavelengths in a multiplate reader. Todetermine minimum staining for calcein-AM (calceinmin), eight wells weretreated with ethanol 30 min before calcein-AM addition. The percentviability is then calculated as[(calcein_(sample)−calcein_(min))/(calcein_(control)−calcein_(min))]×100.

Results

Table 1 shows the effects of standard COMT inhibitors, tolcapone andentacapone, and compounds of general formula I upon mouse liver COMTactivity 3 h after their oral administration (3 mgkg). Also shown intable 1 is the cell viability after 24 h exposure to tolcapone,entacapone and compounds of general formula I (all at 30 μM) in Neuro 2Acells.

TABLE 1 Mouse Liver COMT activity (% control) after 3 mg/kg (oral)administration of compounds listed and Neuro 2A cell viability (% ofviable cells) COMT activity % of viable No. (X)n, (Y)n R3 (% of control)cells Tolcapone 13.9 27.2 Entacapone 79.8 81.4 1 n = m = 0 —CH₃ 59.955.1 2 n = m = 0 —CH₃ 78.8 92.5 3 n = m = 0 —CH₃ 63.6 100.5 4 n = m = 0

42.1 98.3 5 n = m = 0

58.4 93.8 6 n = m = 0

101.0 107.1 7 n = m = 0

14.2 56.9 8 n = m = 0

55.4 106.7 9 n = m = 0

80.6 79.7 10 n = m = 0

95.2 69.3 11 n = m = 0

63.9 105.7 12 n = m = 0

92.9 91.7 13 n = m = 0

102.3 14 n = m = 0

76.8 83.5 15 n = m = 0

79.2 97.1 16 n = m = 0

85.9 64.6 17 n = m = 0

89.9 96.0 18 n = m = 0

21.2 93.4 19 n = m = 0

45.2 100.1 20 n = m = 0

56.6 21 n = m = 0

95.6 22 n = m = 0

111.6 23 n = m = 0

43 41.1 24 n = m = 0

71.8 93.7 25 n = m = 0

23.1 100.2 26 n = m = 0

35.5 110.9 27 n = m = 0

47.5 95.7 28 n = m = 0

11.3 87.0 29 n = m = 0

10.9 62.2 30 n = m = 0

8.8 81.8 31 n = m = 0

0.8 37.2 32 n = m = 0

9.7 26.6 33 n = m = 0

39.8 45.0 34 n = m = 0

88.6 89.0 35 n = m = 0

81.2 88.0 36 n = m = 0

22.9 76.3 37 n = m = 0

42.5 92.3 38 n = m = 0

16.3 86.0 39 X = CH2, n = 1, m = 0

53.8 94.9 40 n = m = 0

55.2 69.1 41 n = m = 0

14 95.1 42 n = m = 0

9.4 96.4 43 X = CH2, n = 1, m = 0

27.2 101.5 44 X = CH2, n = 1, Y= O, m = 1

24.5 45 n = m = 0

30.4 86.6 46 n = m = 0

43.1 53.0 47 n = m = 0

25.2 81.2 Note: *represents the point of attachment of the pyridineN-oxide substituent to the molecule

Compounds of general formula I were also found to be potent inhibitorsof rat liver COMT, the maximal inhibitory effect being achieved within 1h to 3 h after their oral administration (Table 2). The maximalinhibitory effect of entacapone (Ent) and tolcapone (Tolc) were observedwithin 1 h after administration (Table 2). Nine hours afteradministration, entacapone is devoid of COMT inhibitory effects andtolcapone produces minimal inhibitory effects (˜16% inhibition), whereascompounds of general formula I continue to inhibit COMT activity by 22%to 90% of control levels (Table 2).

TABLE 2 Rat Liver COMT activity (% control) after 3 mg/kg (oral)administration of compounds listed. Time (h) Compound 1 3 6 9 Entacapone32.0 74.5 95.2 100.0 Tolcapone 18.3 28.6 56.8 83.9 18 5.2 19.9 43.0 57.429 1.2 18.5 39.7 56.4 30 6.3 34.8 41.2 54.5 41 21.2 9.3 18.8 39.7 42 3.66.1 12.3 30.9 43 16.1 30.6 64.3 77.9 45 1.1 1.2 3.8 8.9 47 10.6 4.0 3.88.2

Table 3 shows percentage changes in plasma levels of L-DOPA and3-O-methyl-L-DOPA (3-OMD) of rats treated with L-DOPA plus benserazideat 2 h after the administration of entacapone, tolcapone and compoundsof general formula I (3 mgkg). L-DOPA plus benserazide were administered1 h before collection of plasma samples. This time-point was chosenbecause it represented the t_(max) for L-DOPA. As can be observed,compounds of general formula I produced significant increases in plasmaL-DOPA accompanied by marked decrease in plasma 3-O-methyl-L-DOPA.

TABLE 3 Effect of of compounds listed (3 mg/kg; oral administration)upon changes (% control) in plasma levels of L-DOPA and3-O-methyl-L-DOPA (3-OMD) of rats treated with L-DOPA plus benserazide.L-DOPA 3-OMD L-Dopa/ Compound % increase % reduction 3-OMD Entacapone68.5 −55.6 3.8 Tolcapone 202.4 −89.0 27.6 18 61.4 −63.9 4.5 29 105.1−80.7 10.6 30 103.5 −75.0 8.1 41 95.2 −72.3 7.1 42 30.7 −43.4 2.3 4374.9 −48.3 3.4 45 100.8 −54.3 4.4 47 102.9 −58.5 4.9

Conclusion

Compounds of general formula I are very potentcatechol-O-methyltransferase (COMT) inhibitors with significantlyreduced toxicity. Compounds of general formula I have potentiallyvaluable pharmaceutical properties in the treatment of some central andperipheral nervous system disorders where inhibition of O-methylation ofcatecholamines may be of therapeutical benefit, such as mood disorders,Parkinson's disease and parkinsonian disorders, restless legs syndrome,gastrointestinal disturbances, edema formation states and hypertension.The possibility to use a potent, long-acting inhibitor with improvedsafety profile opens new perspectives in the treatment of Parkinson'sdisease and parkinsonian disorders, gastrointestinal disturbances, edemaformation states, and hypertension by improving the safety ofnitrocatecholic COMT inhibitors whilst improving or maintaining durationand selectivity of COMT inhibition. This is particularly important whenthinking of treating patients afflicted by Parkinson's disease who aretaking L-DOPA plus a peripheral AADC inhibitor due to the fact that thisis long-term treatment.

The invention disclosed herein is exemplified by the following examplesof preparation, which should not be construed to limit the scope of thedisclosure. Alternative pathways and analogous structures may beapparent to those skilled in the art.

EXAMPLE 13-Nitro-5-[3-(1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol(compound 4, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.5 g,1.32 mmol) in dimethylformamide (5 mL) at room temperature was added1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) in one portion. Afterstirring for one hour, N′-hydroxypyridine-4-carboximidamide (0.208 g,1.52 mmol) was added in one portion and the resulting mixture wasstirred at room temperature overnight. The mixture was then stirred at110° C. for three hours and then allowed to cool to room temperature.The mixture was poured onto ice-water (100 mL) and extracted with 20%isopropanol/dichloromethane. The organic extracts were washed with waterand brine, then dried (Na₂SO₄), filtered and evaporated to leave a solidresidue that was recrystallised from ethanol.4-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridinewas obtained as a beige solid (0.395 g, 62%).b) A stirred solution of the above pyridine compound (0.331 g, 0.689mmol) in dichloromethane (15 mL) was cooled in an ice-water bath andm-chloroperoxybenzoic acid (0.179 g, 1.03 mmol) was added in portions.The resulting mixture was stirred in the cold for thirty minutes andthen at room temperature for thirty minutes whereupon it was cooledagain in an ice-water bath. Further m-chloroperoxybenzoic acid (0.17 g,1.03 mmol) was added and the mixture was then allowed to stir at roomtemperature for one and a half hours. Water (20 mL) was added and theorganic phase was separated and washed with saturated aqueous sodiumbicarbonate solution, water and brine, then dried (Na₂SO₄), filtered andevaporated to leave a yellow oil. Addition of diethyl ether causedformation of a precipitate that was filtered off and recrystallised froma dichloromethaneisopropanol mixture.4-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine1-oxide was obtained as white crystals (0.239 g, 70%).c) A solution of the above dibenzyl ether (0.232 g, 0.468 mmol) indichloromethane (5 mL) was cooled to −78° C. with stirring under argonand treated with boron tribromide (0.586 g, 2.34 mmol) dropwise. Theresulting deep purple suspension was then allowed to stir at roomtemperature for one hour before cooling again to −78° C. The mixture wasquenched by the careful addition of methanol. After stirring at roomtemperature for one hour, the volatiles were evaporated and the residuetreated with ethanol/toluene and re-evaporated. The yellow residue wastriturated with boiling ethanol and filtered whilst still warm to givethe title product as a yellow solid (0.102 g, 69%) of m.p. 280-282° C.

EXAMPLE 23-Nitro-5-[3-(1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol(compound 5, Table 1)

a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.232 g,1.022 mmol) in dimethylformamide (5 ml) at room temperature was added1,1-carbonyldiimidazole (0.174 g, 1.073 mmol) in one portion. Theresulting mixture was stirred for ninety minutes whereuponN′-hydroxypyridine-3-carboximidamide 1-oxide (0.156 g, 1.022 mmol) wasadded in one portion. The resulting mixture was stirred at roomtemperature for two hours, then at 75° C. overnight. After cooling toroom temperature, the mixture was poured onto water (100 mL) and theprecipitate was filtered off, washed with water, then dried in air andrecrystallised from diethyl ether.3-[5-(3,4-dimethoxy-5-nitro-phenyl-[1,2,4]oxadiazol-3-yl]-pyridine1-oxide was obtained as a white solid (0.162 g, 46%).b) To a stirred solution of the dimethyl ether from above (0.153 g,0.445 mmol) in dichloromethane (10 mL) at −78° C. under argon was addedboron tribromide dropwise (0.445 g, 1.779 mmol). The reaction mixturewas allowed to warm to room temperature and stirred for ninety minutesbefore pouring carefully onto water (100 mL). After stirring for twentyminutes, the mixture was extracted with ethyl acetate. The organicextracts were washed with water and brine, dried (Na₂SO₄), filtered andevaporated.2-methoxy-3-nitro-5-[3-(1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-phenolwas obtained as a yellow solid (0.12 g, 82%).c) A stirred suspension of the above methyl ether (0.108 g, 0.327 mmol)in 1,2-dichloroethane (10 mL) at room temperature under argon wastreated with aluminium chloride (0.087 g, 0.654 mmol) followed bypyridine (0.207 g, 2.62 mmol) dropwise. The mixture was then heated atreflux for seven hours whereupon further aluminium chloride (0.087 g,0.654 mmol) and pyridine (0.207 g, 2.62 mmol) were added and the mixturestirred at reflux for a further seven hours. The mixture was thenallowed to cool to room temperature, and poured onto cold 1 Nhydrochloric acid (30 mL). The resulting precipitate was filtered off,washed with water and dried at 50° C. under vacuum. The desired productwas obtained as an orange solid, (0.075 g, 72%) of m.p. 278-280° C.

EXAMPLE 33-Nitro-5-[3-(1-oxy-pyridin-2-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol(compound 6, Table 1)

a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (1.0 g,4.40 mmol) in dimethylformamide (10 mL) at room temperature was added1,1-carbonyldiimidazole (0.821 g, 5.06 mmol) in one portion. Theresulting yellow mixture was allowed to stir for ninety minuteswhereupon N′-hydroxypyridine-2-carboximidamide 1-oxide (0.775 g, 5.06mmol) was added in one portion. The resulting mixture was stirred atroom temperature overnight and then poured onto water (100 mL). Theresulting precipitate was filtered off, washed with water and then takenup in dichloromethane (30 mL). The organic layer was washed with waterand brine, dried (Na₂SO₄), filtered and evaporated to leave a whitesolid (1.37 g, 86%).b) To a stirred suspension of the solid obtained above (1.365 g, 3.77mmol) in tetrahydrofuran (14 mL) at room temperature under argon wasadded a 1 N solution of tetrabutylammonium fluoride in tetrahydrofuran(3.8 mL, 3.8 mmol). The resulting clear yellow solution was allowed tostir at room temperature for seven hours during which time a newprecipitate had formed. The mixture was filtered and the solid waswashed with several portions of cold tetrahydrofuran.2-[5-(3,4-Dimethoxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine1-oxide was obtained as a white solid (0.97 g, 75%).c) To a stirred suspension of the dimethyl ether obtained from above(0.961 g, 2.79 mmol) in dichloromethane (15 mL) at −78° C. under argonwas added boron tribromide (3.5 g, 13.97 mmol) dropwise. The resultingpurple suspension was then allowed to stir at room temperature for sevenhours before being cooled in an ice/water bath. The mixture wascarefully quenched by the addition of methanol. The resulting yellowmixture was allowed to stir at room temperature for one hour before theprecipitate was filtered off and washed with methanol. The solid wastriturated with boiling ethanol and filtered whilst warm. After drying,the desired compound was obtained as an orange solid (0.712 g, 81%) ofm.p. 168° C.

EXAMPLE 4 5-(5-Methyl-[1,2,4]oxadiazol-3-yl)-3-nitro-benzene-1,2-diol(compound 2, Table 1)

a) To a stirred solution of3,4-bis-benzyloxy-N′-hydroxy-5-nitro-benzamidine (1.0 g, 2.54 mmol) indimethylformamide (5 mL) at room temperature was added1,1-carbonyldiimidazole (0.494 g, 3.048 mmol) in one portion and themixture was stirred at room temperature for ninety minutes. Thereupon,acetic acid (0.184 g, 3.067 mmol) was added dropwise and the mixture wasallowed to stir for two hours at room temperature, then at 155° C. forthree hours. The mixture was allowed to cool to room temperature, andpoured onto ice-water (100 mL). Brine (10 mL) was added and theresulting precipitate was removed by filtration, washed with water anddried in air. The solid was then dissolved in dichloromethane (20 mL)and a spatula tip of activated charcoal was added. After stirring fortwenty minutes, the suspension was filtered through celite and thefiltrate was evaporated to leave a yellow oil that solidified onstanding. After recrystallisation from dichloromethane/petroleum ether,3-(3,4-bis-benzyloxy-5-nitrophenyl)-5-methyl-[1,2,4]oxadiazole wasobtained as a pale yellow solid (0.537 g, 51%).b) To a stirred solution of the solid obtained from above (0.128 g,0.307 mmol) in dichloromethane (15 mL) at −78° C. under argon was addedboron tribromide (0.318 g, 1.269 mmol) dropwise. The resulting purplesuspension was allowed to stir at room temperature for one hour, thencooled again to −78° C. The mixture was quenched by the careful additionof methanol, and after stirring at room temperature for one hour, thesolvents were evaporated. The yellow residue was triturated with diethylether, filtered and dried. The desired compound was obtained as a yellowsolid (0.070 g, 96%) of m.p. 169.8-172° C.

EXAMPLE 5 5-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-nitro-benzene-1,2-diol(compound 3, Table 1)

a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.438 g,1.93 mmol) in tetrahydrofuran (10 mL) at room temperature was added1,1-carbonyldiimidazole (0.343 g, 2.12 mmol) in one portion and themixture was stirred at room temperature for one hour, then at 70° C. fortwo hours, whereupon acetic hydrazide (0.157 g, 2.12 mmol) was added.The resulting was stirred at room temperature for thirty minutes, thenat 70° C. for two hours. After cooling to room temperature, the mixturewas poured onto ice-water (100 mL) and the precipitate was filtered offand washed with water. 3,4-Dimethoxy-5-nitro-benzoic acidN′-acetyl-hydrazide was obtained as a white solid (0.296 g, 54%).b) A suspension of the solid obtained above (0.288 g, 1.017 mmol) inphosphorus oxychloride (7 mL) was stirred at 120° C. for two hours, thenallowed to cool to room temperature. The solution was then poured ontoice-water (200 mL), causing formation of a white precipitate. Extractedwith dichloromethane, and the organic extracts were washed with waterand brine, then dried, filtered and evaporated to leave a white solid.Recrystallisation from dichloromethane/petroleum ether gave2-(3,4-dimethoxy-5-nitro-phenyl)-5-methyl-[1,3,4]oxadiazole as whitecrystals (0.151 g, 56%).c) To a stirred solution of the solid obtained above (0.145 g, 0.547mmol) in dichloromethane (10 mL) at −78° C. under argon was added borontribromide (0.685 g, 2.74 mmol) dropwise. The resulting purplesuspension was allowed to stir at room temperature overnight, thencooled again to −78° C. The reaction was quenched by the addition ofmethanol, and after stirring at room temperature for one hour, thevolatiles were evaporated. Toluene (20 mL) was added to the residue andre-evaporated. The residue was triturated with boiling ethanol andfiltered whilst warm to give the desired product as an orange solid(0.107 g, 82%) of m.p. 245-246° C.

EXAMPLE 65-[3-(3,5-Dichloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol(compound 7, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.50 g,1.32 mmol) in dimethylformamide (5 mL) at room temperature was added1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) in one portion, and themixture was stirred for ninety minutes whereupon3,5-dichloro-N′-hydroxy-1-oxyisonicotinamidine (0.337 g, 1.52 mmol) wasadded in one portion. The resulting mixture was stirred at roomtemperature overnight and then poured onto ice-water (100 mL). Brine (10mL) was added and the precipitate was filtered off, washed with waterand dissolved in 30% isopropanol/dichloromethane. The dichloromethanewas then distilled off and the resulting isopropanol suspension wasstored at 0° C. for one hour. The solid was then filtered off, washedwith cold isopropanol and dried to leave a white solid (0.756 g, 98%).b) A portion of this solid (0.664 g, 1.14 mmol) and1,1-carbonyldiimidazole (0.185 g, 1.14 mmol) were dissolved indimethylformamide (10 mL) was stirred at 100° C. for nine hours then atroom temperature overnight. The resulting mixture was poured ontoice-water (100 mL) and then acidified to pH 1-2 by the dropwise additionof 2 N hydrochloric acid. The yellow precipitate that formed wasfiltered off, washed with water and dissolved in 10%isopropanol/dichloromethane (50 mL). The organic phase was dried,filtered and evaporated to dryness. The residue was chromatographed oversilica gel using an ethyl acetate/petroleum ether (1:1) solvent mixture.Homogeneous fractions were pooled and evaporated, and the residue wasrecrystallised from dichloromethaneisopropanol to give2-benzyloxy-4-[3-(3,5-dichloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-6-nitrophenolas a yellow solid (0.263 g, 49%).c) To a stirred suspension of the solid obtained from above (0.24 g,0.505 mmol) in dichloromethane (5 mL) at −78° C. under argon was addedboron tribromide (0.371 g, 1.5 mmol) dropwise. The resulting purplesuspension was allowed to stir at room temperature for one hour, thencooled again to −78° C. and quenched by the addition of methanol. Afterstirring at room temperature for one hour, the solvents were removed byevaporation. The resulting yellow foam was recrystallised fromdichloromethaneisopropanol to give the desired product as a yellow solid(0.153 g, 79%) of m.p. 252-253° C.

EXAMPLE 75-[3-(2-Chloro-1-oxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol(compound 8, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.50 g,1.32 mmol) in dimethylformamide (5 mL) at room temperature was added1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) in one portion and themixture was stirred for one hour, whereupon2-chloro-N′-hydroxy-1-oxy-isonicotinamidine (0.284 g, 1.52 mmol) wasadded in one portion. The resulting mixture was stirred at roomtemperature for thirty minutes, then at 140° C. for four hours. Aftercooling to room temperature, the mixture was poured onto water (100 mL)and acidified to pH 1-2 by the dropwise addition of 2 N hydrochloricacid. The mixture was extracted with ethyl acetate and the organicextracts were washed with water and brine, then dried, filtered andevaporated to leave an orange solid that was recrystallised fromdichloromethaneisopropanol to give4-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-chloro-pyridine1-oxide as pale orange crystals (0.265 g, 38%).b) To a stirred solution of the solid obtained above (0.25 g, 0.471mmol) in dichloromethane (5 mL) at −78° C. under argon was added borontribromide (0.59 g, 2.36 mmol) dropwise. The resulting deep purplesuspension was allowed to stir at room temperature for one hour, thencooled again to −78° C. The reaction was quenched by the addition ofmethanol, and after stirring at room temperature for one hour, thesolvents were removed by evaporation. Ethanol (5 mL) and toluene (20 mL)were added to the residue and re-evaporated. The residue was trituratedwith boiling ethanol and filtered while warm to give the desired productas yellow crystals (0.12 g, 72%) which decomposed above 300° C.

EXAMPLE 82,5-Dichloro-3-(5-(3,4-dihydroxy-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine1-oxide

a) To a stirred suspension of 3-hydroxy-4-methoxy-2-nitrobenzoic acid(0.900 g, 4.22 mmol) in N,N-dimethylacetamide (10.35 mL) at roomtemperature was added 1,1-carbonyldiimidazole (1.540 g, 9.506 mmol) in7.65 ml of N,N-dimethylacetamide dropwise. After stirring for threehours, (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (1.19 g,5.107 mmol) was added in 2.7 ml of N,N-dimethylacetamide in one portion.The resulting mixture was stirred for one hour and forty five minutesthen heated at 135° C. for one hour. The reaction mixture was pouredonto ice/2N HCl mixture. The precipitate was filtered off, washed withwater and dried under vacuum to give a yellow solid. Recrystallisationfrom dichloromethaneisopropanol gave3-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-6-methoxy-2-nitrophenolas a yellow solid (0.317 g, 18%).b) To a stirred suspension of the solid obtained above (0.315 g, 0.766mmol) in dichloromethane (4.3 mL) at room temperature was added ureahydrogen peroxide addition complex (0.231 g, 2.451 mmol). The resultingsuspension was cooled to 0° C. and trifluoroacetic anhydride (0.483 g,2.30 mmol) was added dropwise. The mixture was allowed to stir at roomtemperature for twenty four hours, then water was added and stirred forone hour. The precipitate was filtered off, washed with water and dried.The crude product was chromatographed in dichloromethane/methanol (99:1)mixture. Evaporation of pure fractions gave2,5-dichloro-3-(5-(3-hydroxy-4-methoxy-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine1-oxide as yellow crystals (0.195 g, 59%).c) To a stirred suspension of the solid obtained above (0.143 g, 0.335mmol) in N-Methylpyrrolidone (2.5 mL) at 0° C. under argon was addedaluminium chloride (0.056 g, 0.42 mmol) in one portion followed by theaddition of pyridine (0.106 g, 1.34 mmol). The resulting solution washeated at 60° C. for twenty-five minutes, then cooled again to roomtemperature and poured onto ice/2N HCl mixture. After stirring at roomtemperature for forty-five minutes, the precipitate was filtered off,washed with water and dried under vacuum. The crude product wasrecrystallized from dichloromethaneisopropanol mixture. After drying,the desired compound was obtained as yellow crystals (0.101 g, 73%) ofm.p. 230° C. (dec.)

EXAMPLE 9-17

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriateN-hydroxy-1-oxy-isonicotinamidines, the following compounds wereprepared:

-   3-Nitro-5-[3-(1-oxy-2-phenyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 264-264.8° C. (compound 9, Table 1)-   5-[3-(2-Furan-3-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-dial,    of m.p. 304-305° C. (compound 10, Table 1)-   5-[3-(2-Morpholin-4-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-dial,    of m.p. 277-280° C. (compound 11, Table 1)-   3-Nitro-5-[3-(1-oxy-2-thiomorpholin-4-yl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 260-262° C. (compound 12, Table 1)-   3-Nitro-5-[3-(1-oxy-2-phenyl    sulfanyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-dial, of    m.p. 299-301° C. (compound 13, Table 1)-   3-Nitro-5-[3-(1-oxy-2-phenoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 245-246° C. (compound 14, Table 1)-   5-[3-(2,6-Dimethyl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol    of, m.p. 280-282° C. (compound 15, Table 1)-   5-[3-(2-Methanesulfonyl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol    of, m.p. 282-285° C. (compound 16, Table 1)-   5-[3-(2-Methyl    sulfanyl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol    of, m.p. 239-240° C. (compound 17, Table 1)

EXAMPLE 183-Nitro-5-[3-(1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol(compound 18, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.291g, 0.769 mmol) in dimethylformamide (5 mL) at room temperature was added1,1-carbonyldiimidazole (0.131 g, 0.808 mmol) in one portion. Afterstirring for ninety minutes,N′-hydroxy-1-oxy-4-trifluoromethyl-nicotinamidine (0.17 g, 0.769 mmol)was added in one portion. The resulting mixture was stirred for twohours and then poured onto ice-water (100 mL). The precipitate wasfiltered off, washed with water and dried in air to give a white solid(0.192 g, 43%).b) To a stirred solution of the solid obtained above (0.192 g, 0.33mmol) in tetrahydrofuran (10 mL) at room temperature under argon, wasadded a 1 N solution of tetrabutylammonium fluoride in tetrahydrofuran(1.2 mL, 1.2 mmol) dropwise. After stirring at room temperatureovernight, the mixture was poured onto water (100 mL) and extracted withdichloromethane. The organic extracts were washed with water and brine,dried (Na₂SO₄), filtered and evaporated. The residue was chromatographedover silica gel using a dichloromethane/methanol (99:1) solvent mixtureas eluent. Homogenous fractions were pooled and evaporated and theresidue then recrystallised from dichloromethaneisopropanol.3-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-4-trifluoromethyl-pyridine1-oxide was obtained as a white solid (0.092 g, 49%).c) To a stirred solution of the solid obtained above (0.09 g, 0.16 mmol)in dichloromethane (5 mL) at −78° C. under argon was added borontribromide (0.16 g, 0.64 mmol) dropwise. The resulting purple suspensionwas allowed to stir at room temperature for one hour, then cooled againto −78° C. and carefully quenched by the addition of water. Afterstirring at room temperature for one hour, the precipitate was filteredoff, washed with water and dried at 50° C. under vacuum to afford thedesired compound as yellow crystals (0.048 g, 79%) of m.p. 239-240° C.

EXAMPLE 19-35

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriateN′-hydroxy-1-oxy-isonicotinamidines, the following compounds wereprepared:

-   5-[3-(5-Bromo-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 258-260° C. (compound 19, Table 1)-   5-[3-(6-Methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 325-326° C. (compound 20, Table 1)-   5-[3-(4-Methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 297° C. (compound 21, Table 1)-   3-Nitro-5-[3-(1-oxy-5-phenyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 288-289° C. (compound 22, Table 1)-   5-[3-(6-Chloro-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 268-270° C. (compound 23, Table 1)-   5-[3-(2-Chloro-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 265-267° C. (compound 24, Table 1)-   5-[3-(2-Chloro-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 218-220° C. (compound 25, Table 1)-   5-[3-(2-Morpholin-4-yl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 175-177° C. (compound 26, Table 1)-   5-[3-(6-Methylsulfanyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 264-266° C. (compound 27, Table 1)-   3-Nitro-5-[3-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 269.5-271.3° C. (compound 28, Table 1)-   5-[3-(2-Methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 240-242° C. (compound 29, Table 1)-   5-[3-(6-Methyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 250-252.5° C. (compound 30, Table 1)-   5-[3-(2,6-Dimethyl-1-oxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 252-253° C. (compound 31, Table 1)-   5-[3-(2-Methyl-1-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 256-256.5° C. (compound 32, Table 1)-   5-[3-(6-Methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 237-239° C. (compound 33, Table 1)-   3-Nitro-5-[3-(1-oxy-quinolin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 306-307° C. (compound 34, Table 1)-   3-Nitro-5-[3-(1-oxy-quinolin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 276-277° C. (compound 35, Table 1)-   3-Nitro-5-[3-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 253-254° C. (compound 42, Table 1)

EXAMPLE 365-[3-(2-Bromo-6-methyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol(compound 36, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (1.355g, 3.576 mmol) in dimethylformamide (10 mL) at room temperature wasadded 1,1-carbonyldiimidazole (0.667 g, 4.113 mmol) in one portion.After stirring for ninety minutes,2-bromo-N′-hydroxy-6-methylnicotinamidine (0.946 g, 4.113 mmol) wasadded and the mixture was stirred overnight then poured onto water (100mL). Brine (10 mL) was added and the precipitate was filtered off,washed with water and dissolved in dichloromethane (50 mL). The organiclayer was washed with water and brine, then dried (Na₂SO₄), filtered andevaporated to leave a white foam (1.91 g, 90%).b) To a solution of the solid obtained above (1.91 g, 3.23 mmol) indimethylformamide (30 mL) was added 1,1-carbonyldiimidazole (0.576 g,3.55 mmol) and the resulting mixture was stirred at 120° C. for threehours, then allowed to cool to room temperature. Poured onto ice-water(150 mL) and acidified to pH 1-2 by the dropwise addition of 2 Nhydrochloric acid. The mixture was extracted with dichloromethane andthe organic extracts were washed with water and brine, then dried(Na₂SO₄), filtered and evaporated to leave an orange solid.Recrystallisation from dichloromethane/ethanol gave3-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-6-methyl-pyridineas an orange solid (0.702 g, 38%).c) To a stirred solution of the solid obtained above (0.609 g, 1.063mmol) in dichloromethane (15 mL) at room temperature was added ureahydrogen peroxide addition complex (0.525 g, 5.579 mmol). The resultingsuspension was cooled to 0° C. and trifluoroacetic anhydride (1.12 g,5.314 mmol) was added dropwise. The mixture was allowed to stir at roomtemperature for five hours, then the insoluble material was filtered offand washed with a small volume of dichloromethane. The combined filtratewas stirred with a 10% aqueous solution of sodium metabisulphite (10 mL)for fifteen minutes to destroy excess peroxides, then the phases wereseparated. The organic phase was washed with water, a saturated aqueoussolution of sodium bicarbonate, water again and brine, then dried(Na₂SO₄), filtered and evaporated to leave a white solid.Recrystallisation twice from dichloromethane/ethanol gave3-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-6-methyl-pyridine1-oxide as white crystals (0.344 g, 55%).d) To a stirred solution of the solid obtained above (0.337 g, 0.572mmol) in dichloromethane (10 mL) at −78° C. under argon was added borontribromide (0.717 g, 2.86 mmol) dropwise. The resulting purplesuspension was stirred at room temperature for one hour, then cooledagain to −78° C. and quenched by the addition of methanol. Afterstirring at room temperature for one hour, the solvents were evaporated.Ethanol (5 mL) and toluene (20 mL) were added to the residue andre-evaporated. The residue was stirred in boiling ethanol and filteredwhile still warm. After drying, the desired compound was obtained asorange crystals (0.187 g, 80%) of m.p. 246-247° C.

EXAMPLE 37-41

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriateN′-hydroxy-nicotinamidines, the following compounds were prepared:

-   5-[3-(2-Chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 234-235° C. (compound 37, Table 1)-   5-[3-(2-Bromo-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,    of m.p. 205-207° C. (compound 38, Table 1)-   3-Nitro-5-[3-(1′-oxy-pyridin-3-ylmethyl)-[1,2,4]oxadiazol-5-yl]-benzenediol,    of m.p. 232° C. (compound 39, Table 1)-   3-Nitro-5-[3-(1′-oxy-6-trifluoromethyl-pyridine-3-ylmethyl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 195.2° C. (compound 43, Table 1)-   3-Nitro-5-[3-(1′-oxy-5-trifluoromethyl-pyridin-2-yloxymethyl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    of m.p. 222° C. (compound 44, Table 1)

EXAMPLE 425-[3-(2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol(compound 40, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.945g, 2.49 mmol) in dimethylformamide (10 mL) at room temperature was added1,1-carbonyldiimidazole (0.465 g, 2.87 mmol) in one portion, and theresulting mixture was stirred for two hours, whereupon2-bromo-N′-hydroxy-4,5,6-trimethyl-nicotinamidine (0.74 g, 2.87 mmol)was added in one portion. The resulting mixture was allowed to stir atroom temperature overnight, and then poured onto water (150 mL). Brine(10 mL) was added, and the resulting precipitate was filtered off andwashed with water. The solid was then dissolved in dichloromethane (50mL) and the organic phase was washed with water and brine, then dried,filtered and evaporated to leave an off-white solid (1.40 g, 91%).b) To a stirred solution of the solid obtained above (1.39 g, 2.245mmol) in tetrahydrofuran (20 mL) at room temperature under argon wasadded a 1 N solution of tetrabutylammonium fluoride in tetrahydrofuran(2.47 mL, 2.47 mmol). After stirring at room temperature overnight, thealmost black reaction mixture was poured onto water (150 mL) andextracted with dichloromethane. The organic extracts were washed withwater and brine, then dried, filtered and evaporated to leave a brownoil. Addition of dichloromethane (4 mL) and diethyl ether (4 mL) causedformation of a precipitate that was filtered off and recrystallised fromisopropanol.3-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-4,5,6-trimethyl-pyridinewas obtained as a beige solid (0.879 g, 65%).c) To a stirred solution of the pyridine obtained from above (0.621 g,1.033 mmol) in dichloromethane (20 mL) at room temperature was addedurea hydrogen peroxide complex (1.018 g, 10.82 mmol) in one portion. Theresulting suspension was cooled in an ice-water bath and trifluoroaceticanhydride (2.23 g, 10.62 mmol) was added dropwise. The resultingsuspension was stirred in the cold for fifteen minutes and then allowedto stir at room temperature overnight. The insoluble material was thenfiltered off and washed with a small volume of dichloromethane. Thecombined filtrate was stirred with a 10% aqueous solution of sodiummetabisulphite for fifteen minutes and then the phases were separated.The organic phase was washed with water, a saturated aqueous solution ofsodium bicarbonate, water again and brine, then dried, filtered andevaporated to leave a foamy pale orange solid. This solid waschromatographed over silica gel using a petroleum ether/ethyl acetate(1:1) mixture as eluent. Homogenous product containing fractions werepooled and evaporated.3-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-4,5,6-trimethyl-pyridine1-oxide was obtained as a foamy pale yellow solid (0.342 g, 54%).d) To a stirred solution of the solid obtained above (0.325 g, 0.527mmol) in dichloromethane (10 mL) at −78° C. under argon was added borontribromide (0.66 g, 2.633 mmol) dropwise. The resulting deep purplesuspension was allowed to stir at room temperature for one hour, thencooled again to 78° C. and carefully quenched by the dropwise additionof methanol. After stirring at room temperature for one hour, thesolvents were removed by evaporation. Toluene (20 mL) and ethanol (5 mL)were added to the residue and re-evaporated. The resulting yellow solidwas triturated with boiling ethanol (15 mL) and filtered whilst warm.The desired product was obtained as a yellow solid (0.172 g, 75%) ofm.p. 242-243° C.

EXAMPLE 43-46

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriateN′-hydroxy-nicotinamidine, the following compounds were prepared:

-   5-[3-(2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,    m.p. 246-247.3° C. (compound 41, Table 1)-   5-[3-(2,5-Dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,    m.p. 237-240° C. (compound 45, Table 1)-   3-Nitro-5-[3-(4,5,6-trimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol,    m.p. 255-256° C. (compound 46, Table 1)-   5-[3-(2-Bromo-5-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol,    m.p. 227-228° C. (compound 47, Table 1)

EXAMPLE 47

As an example of a compound of the general formula (I) having a2H-pyrazol-1,5-diyl moiety as central unit,3-nitro-5-[2-(1-oxy-2-trifluormethyl-pyridin-3-yl)-2H-pyrazol-3-yl]-benzene-1,2-diolwas prepared by the following procedure:

a) To a stirred solution of1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-prop-2-en-1-one (0.5 g,1.79 mmol) and (2-trifluoromethyl-pyridin-3-yl)-hydrazine (0.33 g, 1.87mmol) in ethanol (10 mL) was added 10 drops of concentrated hydrochloricacid and the mixture was heated at reflux for two hours. The mixture wasallowed to cool to room temperature and the resulting precipitate wasfiltered off, washed with ethanol and dried to give3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine,0.58 g (82%).b) To a solution of3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine(0.50 g, 1.27 mmol) in dichloromethane (10 mL) cooled in an ice-waterbath was added urea-hydrogen peroxide complex (0.26 g, 2.76 mmol) in oneportion followed by trifluoroacetic anhydride (0.53 g, 2.52 mmol)dropwise. The resulting mixture was allowed to stir at room temperatureovernight and then the insoluble material was filtered off. The filtratewas washed with water and brine, then dried over anhydrous sodiumsulphate, filtered and evaporated to leave an off-white solid.Recrystallisation from ethanol afforded3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine1-oxide, 0.34 g (65%).c) A suspension of3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine1-oxide (0.3 g, 0.73 mmol) in 48% aqueous hydrobromic acid (10 mL) wasstirred at 140° C. for one hour and then allowed to cool to roomtemperature. The mixture was then poured onto ice-water (100 mL) and theresulting yellow precipitate was filtered off, washed with water anddried to give3-nitro-5-[2-(1-oxy-2-trifluormethyl-pyridin-3-yl)-2H-pyrazol-3-yl]-benzene-1,2-diol,0.16 g (57%).

EXAMPLE 48

As an example of a compound of the general formula (I) having a1,3,4-oxadiazol-2,5-diyl moiety as central unit,3-nitro-5-[5-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diolwas prepared by the following procedure:

a) A mixture of 3,4-dimethoxy-5-nitrobenzoic acid (0.53 g, 2.34 mmol)and 1,1-carbonyldiimidazole (0.42 g, 2.59 mmol) was heated intetrahydrofuran (10 mL) at reflux for three hours and then cooled toroom temperature. 2-Trifluoromethyl-nicotinic acid hydrazide (0.53 g,2.57 mmol) was added in one portion and the yellowish mixture wasstirred at reflux overnight and then allowed to cool to roomtemperature. The mixture was poured onto cold water (100 mL) and thecopious precipitate was filtered off, washed with water and dried togive 2-trifluoromethyl-nicotinic acidN′-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide, 0.71 g (73%).b) A suspension of 2-trifluoromethyl-nicotinic acidN′-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide (0.60 g, 1.44 mmol) inphosphorus oxychloride (10 mL) was stirred at 130° C. for three hours,becoming a pale yellow solution. The mixture was allowed to cool to roomtemperature and then poured onto ice-water (200 mL). The whiteprecipitate was filtered off, washed with water and dried to give3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine,0.48 g (84%).c) To a stirred solution of3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine(0.45 g, 1.13 mmol) in dichloromethane (10 mL)) cooled in an ice-waterbath was added urea hydrogen peroxide complex (0.23 g, 2.45 mmol) in oneportion followed by trifluoroacetic anhydride (0.47 g, 2.24 mmol)dropwise. The resulting mixture was allowed to stir at room temperatureovernight and then the insoluble material was filtered off. The filtratewas washed with water and brine, then dried over anhydrous sodiumsulphate, filtered and evaporated to leave an off-white solid.Recrystallisation from ethanol afforded3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine1-oxide, 0.39 g (83%).d) A suspension of3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine1-oxide (0.30 g, 0.73 mmol) in a mixture of 48% hydrobromic acid (5 mL)and 30% hydrogen bromide in acetic acid (5 mL) was heated at 140° C.overnight and then allowed to cool to room temperature. Afterevaporation to dryness under reduced pressure, toluene (10 mL) was addedto the residue and re-evaporated under reduced pressure. The resultingsolid was recrystallised from isopropanol to give3-nitro-5-[5-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diolas a yellow solid, 0.19 g, (68%).

EXAMPLE 49

As an example of a compound of the general formula (I) having apyrimidin-2,4-diyl moiety as central unit,3-nitro-5-[2-(1-oxy-2-trifluoromethyl-pyridine-3-yl)-pyrimidin-4-yl]-benzene-1,2-diolwas prepared by the following procedure:

a) A stirred suspension of1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-prop-2-en-1-one (0.28g, 1.0 mmol), 1-oxy-2-trifluoromethyl-nicotinamidine (0.31 g, 1.5 mmol)and potassium tert-butoxide (0.17 g, 1.5 mmol) in absolute ethanol (5mL) was heated to 80° C. in a sealed tube for one hour and then allowedto cool to room temperature. The mixture was poured onto cold water (100mL) and the resulting precipitate was filtered off, washed with waterand dried to give4-(3,4-dimethoxy-5-nitro-phenyl)-2-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-pyrimidine,0.31 g (73%).b) A suspension of4-(3,4-dimethoxy-5-nitro-phenyl)-2-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-pyrimidine(0.25 g, 0.59 mmol) in 48% hydrobromic acid (5 mL) was stirred at 140°C. for four hours and then allowed to cool to room temperature. Themixture was poured onto ice-water (100 mL) and the resulting filtratewas filtered off, washed with water and dried to give3-nitro-5-[2-(1-oxy-2-trifluoromethyl-pyridine-3-yl)-pyrimidin-4-yl]-benzene-1,2-diol,0.21 g (90%).

EXAMPLE 50

As an example of a compound of the general formula (I) having abenzene-1,3-diyl moiety as central unit,5-nitro-3′-(1-oxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-3,4-diol wasprepared by the following procedure:

a) To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0g, 3.87 mmol) and 2-(3-bromo-phenyl)-6-trifluoromethyl-pyridine 1-oxide(1.12 g, 3.52 mmol) in toluene (10 mL) and ethanol (1 mL) at roomtemperature under argon was added 2 N aqueous sodium carbonate solution(5.41 mL, 10.82 mmol) followed by tetrakis(triphenylphosphine)palladium(0.22 g, 0.19 mmol). The resulting mixture was stirred at 90° C. for twohours and then allowed to cool to room temperature. The phases wereseparated and the aqueous phase was extracted with toluene (5 mL). Thecombined organic phases were washed with water and brine, then driedover anhydrous sodium sulphate and filtered. Evaporation of the solventleft a brown oil that was chromatographed over silica gel (petroleumether/ethyl acetate, 9:1) to give2-(4′-benzyloxy-3′-methoxybiphenyl-3-yl)-6-trifluoromethyl-pyridine1-oxide as a clear oil, 1.11 g (70%).b) To a solution of2-(4′-benzyloxy-3′-methoxybiphenyl-3-yl)-6-trifluoromethyl-pyridine1-oxide (1.10 g, 2.44 mmol) in dichloromethane (20 mL) cooled in anice-water bath was added a 30% solution of hydrogen bromide in aceticacid (4 mL, 20 mmol) dropwise. The resulting solution was allowed tostir at room temperature for six hours then poured onto ice-water (100mL). The phases were separated and the aqueous phase was extracted withdichloromethane (10 mL). The combined organic layers were washed withwater and brine, then dried over anhydrous sodium sulphate and filtered.Evaporation of the solvent left a brown oil that was chromatographedover silica gel (petroleum ether/ethyl acetate, 4:1) to give3-methoxy-3′-(1-oxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol as aclear oil, 0.57 g (65%).c) To a solution of3-methoxy-3′-(1-oxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol (0.50g, 1.38 mmol) in acetic acid (10 mL) at room temperature was added 60%nitric acid (0.12 mL, 1.52 mmol) dropwise. The resulting mixture wasallowed to stir for thirty minutes then poured onto ice-water (100 mL)and the resulting precipitate was filtered off, washed with water anddried. After chromatography over silica gel (petroleum ether/ethylacetate, 2:1),5-methoxy-3-nitro-3′-(1-oxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-olwas obtained as a yellow solid, 0.34 g (60%).d) To a stirred solution of5-methoxy-3-nitro-3′-(1-oxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol(0.30 g, 0.738 mmol) in 1,2-dichloroethane (10 mL) cooled in anice-water bath was added aluminium chloride (0.123 g, 0.922 mmol) in oneportion followed by pyridine (0.233 g, 2.95 mmol) dropwise. Theresulting red suspension was stirred at 80° C. for two hours, thencooled to room temperature and poured onto cold 2 N aqueous hydrochloricacid (100 mL). The precipitate was filtered off, washed with water anddried to give5-nitro-3′-(1-oxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-3,4-diol,0.17 g, (59%).

EXAMPLE 51

As an example of a compound of the general formula (I) having a carbonylmoiety as central unit,(3,4-dihydroxy-5-nitro-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanonewas prepared by the following procedure:

a) To a solution of 4-benzyloxy-3-methoxy-bromobenzene (2.0 g, 6.82mmol) in tetrahydrofuran (50 mL) at −78° C. under argon was added 2 Nbutyllithium solution in hexanes (3.75 mL, 7.5 mmol) dropwise. Theresulting mixture was allowed to stir for one hour, whereupon a solutionof N-methoxy-N-methyl-2-trifluoromethyl-nicotinamide (1.76 g, 7.5 mmol)in tetrahydrofuran (20 mL) was added dropwise. The mixture was thenallowed to reach room temperature over two hours, then poured onto cold2 N aqueous hydrochloric acid (150 mL). The mixture was extracted withdiethylether, and the combined organic layers were washed with water andbrine, dried over anhydrous sodium sulphate and filtered. Evaporation ofthe solvent left a brown oil that was chromatographed over silica gel(petroleum ether/ethyl acetate, 2:1) to give(4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridin-3-yl)-methanone,1.72 g (65%).b) To a stirred solution of(4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridin-3-yl)-methanone(1.60 g, 4.13 mmol) in dichloromethane (20 mL) cooled in an ice-waterbath was added urea hydrogen peroxide complex (0.85 g, 9.08 mmol) in oneportion followed by trifluoroacetic anhydride (1.73 g, 8.26 mmol)dropwise. The resulting mixture was then allowed to stir at roomtemperature overnight, whereupon insoluble material was filtered off andwashed with dichloromethane (5 mL). The combined filtrate was washedwith water and brine, then dried over anhydrous sodium sulphate andfiltered. Evaporation of the solvent left an orange solid that wasrecrystallised from ethanol to give(4-benzyloxy-3-methoxy-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanone,1.0 g (60%).c) To a stirred solution of(4-benzyloxy-3-methoxy-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanone(0.95 g, 2.36 mmol) in dichloromethane cooled in an ice-water bath wasadded dropwise a 30% solution of hydrogen bromide in acetic acid (3.54mL, 17.7 mmol). The resulting solution was allowed to stir at roomtemperature overnight then poured onto ice-water (100 mL). The phaseswere separated and the aqueous phase extracted with dichloromethane (10mL). The combined organic layers were washed with water and brine, thendried over anhydrous sodium sulphate and filtered. Evaporation of thesolvent left a brown oil that was chromatographed over silica gel(petroleum ether/ethyl acetate, 1:1) to give(4-hydroxy-3-methoxy-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanoneas a colourless solid, 0.59 g (80%).d) To a solution of(4-hydroxy-3-methoxy-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanone(0.50 g, 1.59 mmol) in acetic acid (10 mL) at room temperature was added60% nitric acid (0.14 mL, 1.75 mmol) dropwise. The resulting mixture wasallowed to stir for thirty minutes then poured onto ice-water (100 mL)and the resulting precipitate was filtered off, washed with water anddried. Recrystallisation from ethanol afforded(4-hydroxy-3-methoxy-5-nitro-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanoneas a yellow solid, 0.33 g (58%).e) To a stirred solution of(4-hydroxy-3-methoxy-5-nitro-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanone(0.30 g, 0.84 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-waterbath was added aluminium chloride (0.14 g, 1.05 mmol) in one portionfollowed by pyridine (0.26 g, 3.35 mmol) dropwise. The resulting redsuspension was stirred at 80° C. for two hours, then cooled to roomtemperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL).The precipitate was filtered off, washed with water and dried to give(3,4-dihydroxy-5-nitro-phenyl)-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-methanone,0.19 g, (66%).

EXAMPLE 52

As an example of a compound of the general formula (I) having a(Z)-1-cyanoethen-1,2-diyl moiety as central unit,3-(3,4-dihydroxy-5-nitro-phenyl)-2-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acrylonitrilewas prepared by the following procedure:

a) A suspension of vanillin (1.0 g, 6.57 mmol),(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.33 g, 6.57 mmol)and piperidine (0.71 mL, 7.23 mmol) in absolute ethanol (10 mL) wasstirred at reflux for forty-eight hours and then allowed to cool to roomtemperature. The resulting precipitate was filtered off, washed withwater and dried. Recrystallisation from isopropanol afforded3-(4-hydroxy-3-methoxy-phenyl)-2-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acrylonitrileas white crystals, 0.95 g (43%).b) To a solution of3-(4-hydroxy-3-methoxy-phenyl)-2-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acrylonitrile(0.90 g, 2.68 mmol) in acetic acid (20 mL) was added 60% nitric acid(0.23 mL, 2.95 mmol) dropwise. The resulting mixture was allowed to stirat room temperature for thirty minutes then poured onto ice-water (100mL). The yellow precipitate was filtered off, washed with water anddried. Recrystallisation from isopropanol afforded3-(4-hydroxy-3-methoxy-5-nitro-phenyl)-2-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acrylonitrileas a yellow solid, 0.63 g, (62%).c) To a stirred solution of3-(4-hydroxy-3-methoxy-5-nitro-phenyl)-2-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acrylonitrile(0.55 g, 1.44 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-waterbath was added aluminium chloride (0.24 g, 1.80 mmol) in one portionfollowed by pyridine (0.46 g, 5.77 mmol) dropwise. The resulting redsuspension was stirred at 80° C. for two hours, then cooled to roomtemperature and poured onto cold 2 N aqueous hydrochloric acid (100 mL).The precipitate was filtered off, washed with water and dried to give3-(3,4-dihydroxy-5-nitro-phenyl)-2-(1-oxy-6-trifluoromethyl-pyridin-3-yl)-acrylonitrile,0.32 g (60%).

EXAMPLE 53

As an example of a compound of the general formula (I) having a1H-imidazol-1,5-diyl moiety as central unit,2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine1-oxide was prepared by the following procedure:

a) To a stirred solution of 2-amino-5-(trifluoromethyl)pyridine 1-oxide(0.445 g, 2.5 mmol) in a mixture of ethanol (12.5 mL) and acetic acid(0.25 mL) at room temperature was added3,4-dimethoxy-5-nitrobenzaldehyde (0.53 g, 2.5 mmol). The reaction washeated at reflux temperature for two hours then ethanol was evaporated.The oily residue was dissolved in a mixture of methanol (17 mL) and1,2-dimethoxyethane (7.5 mL), whereupon1-(isocyanomethylsulfonyl)-4-methylbenzene (TOSMIC) (0.73 g, 3.75 mmol)and potassium carbonate (0.69 g, 5 mmol) were added in one portion. Theresulting mixture was stirred at reflux temperature for 3 hours. Thereaction was evaporated to dryness, and then taken up in dichloromethane(50 ml). The organic phase was washed with water (50 mL) and then driedover anhydrous magnesium sulphate, filtered and evaporated to leavebrown oil. Column chromatography over silica gel (petroleum ether-ethylacetate 9:1) gave2-(5-(3,4-dimethoxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine1-oxide, 0.56 g (55%).b)2-(5-(3,4-Dimethoxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine1-oxide (0.41 g, 1 mmol) was heated at 140° C. in 48% aqueous hydrogenbromide (6 mL) for 2.5 hours. The dark homogeneous solution was cooledto room temperature and volatiles were removed by evaporation to leave apale brown crystalline solid that was dried over P₂O₅ under vacuum.Trituration of the resulting solid with diethyl ether gave2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine1-oxide as a yellow crystalline solid, 0.27 g (71%).

EXAMPLE 54

As an example of a compound of the general formula (I) having aisoxazo-3,5-diyl moiety as central unit,3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide was prepared by the following procedure:

a) To a stirred suspension of(E)-3-(3-(3,4-dimethoxy-5-nitrophenyl)acryloyl)-2-(trifluoromethyl)pyridine1-oxide (1.19 g, 3 mmol) in ethanol (15 mL) was added 50% aqueoushydroxylamine solution (0.74 mL, 4.5 mmol) and the mixture was heated to80° C. After stirring for 1 hour, a fine precipitate began to separatefrom the reaction mixture. After cooling to room temperature the yellowprecipitate was filtered off, washed with ethanol and dried under vacuumto give3-(3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxy-4,5-dihydroisoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide, 0.94 g (73%).b)3-(3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxy-4,5-dihydroisoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide (2.14 g, 5 mmol) was heated in 20 mL of ethyl acetate to 70° C.To the resulting slurry was added trifluoroacetic acid (0.74 g, 6.5mmol) dropwise. After 10 minutes, the reaction was evaporated to drynessand the residue was recrystallised from isopropanol to give3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide, 1.27 g (62%).c) 3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide (0.81 g, 2 mmol) was taken up in dichloromethane (15mL) and the yellowish suspension was cooled to −78° C. under argonwhereupon boron tribromide (4.5 g, 18 mmol) was added dropwise. Thereddish reaction mixture was allowed to warm to room temperature andstirred for 18 hours, then carefully poured into ice-water (100 mL) andallowed to stir for 1 hour. The yellow precipitate was filtered off,washed with water and dried over P₂O₅ under vacuum. Trituration withboiling ethanol gave3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine1-oxide as a yellow solid, 0.49 g (64%).

EXAMPLE 55

As an example of a compound of the general formula (I) having afuran-2,4-diyl moiety as central unit,3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine-1-oxidewas prepared by the following procedure:

a) To a stirred solution of3-(3-ethoxy-3-oxopropanoyl)-2-(trifluoromethyl)pyridine-1-oxide (1.39 g,5 mmol) in pyridine (25 mL) was added2-bromo-1-(3,4-dimethoxy-5-nitrophenyl)ethanone (1.67 g, 5.5 mmol). Thereaction mixture was heated to 70° C. and stirred for 5 hours, thencooled to room temperature and poured onto 6 N aqueous HCl (100 mL). Theprecipitate was filtered off, washed with water and dried over P₂O₅under vacuum. The solid was recrystallised fromdichloromethane/ispropanol to give crude3-(4-(3,4-dimethoxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine1-oxide, 1.05 g (43%).b)3-(4-(3,4-Dimethoxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoro-methyl)pyridine-1-oxide(482 mg, 1 mmol) was taken up in dichloromethane (8 mL). The yellowishsuspension was cooled to −78° C. under argon and boron tribromide (0.85mL, 9 mmol) was added dropwise. The reddish reaction mixture was allowedto warm to room temperature and stirred for 18 hours and then carefullypoured into ice-water (100 mL) and stirred for 1 hour. The yellowprecipitate was filtered off, washed with water and dried over P₂O₅under vacuum. Recrystallisation of the solid from ethanol gave3-(4-(3,4-Dihydroxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine1-oxide as a yellow solid, 0.31 g (68%).

EXAMPLE 56

As an example of a compound of the general formula (I) having aoxazol-2,4-diyl moiety as central unit,3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide was prepared by the following procedure:

a) To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoethyl acetate(4.24 g, 15 mmol) in xylene (30 mL) were added3-carbamoyl-2-(trifluoromethyl)pyridine 1-oxide (3.40 g, 16.5 mmol) andboron trifluoride etherate (0.18 mL, 15 mmol). The resulting yellowsolution was heated to reflux for 18 hours and then cooled to roomtemperature. After evaporation of the solvent, the residue waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic phase was separated, washed with brine and thedried over anhydrous magnesium sulphate, filtered and evaporated. Thepure 3-(4-(3,4-dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine 1-oxide was obtained by column chromatography over silica gel(petroleum ether/ethylacetate 2:1) as a pale yellow solid, 2.58 g (42%).b)3-(4-(3,4-Dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide (1.23 g, 3 mmol) was taken up in dichloromethane (25 mL). Theyellowish suspension was cooled to −78° C. under argon and borontribromide (2.55 mL, 27 mmol) was added dropwise. The red reactionmixture was allowed to warm to room temperature and stirred for 18hours. It was then carefully poured into ice-water (100 mL) and stirredfor 1 hour. The resulting yellow precipitate was filtered off, washedwith water and dried over P₂O₅ under vacuum. The solid wasrecrystallized from ethanol to give3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine1-oxide as a yellow solid, 0.65 g, (57%).

EXAMPLE 57

As an example of a compound of the general formula (I) having a1,2,4-triazin-3,5-diyl moiety as central unit,3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine1-oxide was prepared by the following procedure:

a) To a stirred solution of (Z)-3-carbamohydrazonoyl-2-(trifluoromethyl)pyridine 1-oxide (1.10 g, 5 mmol) in ethanol (30 mL) was added2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoacetaldehyde (1.19 g, 5 mmol). Thereaction mixture was heated to reflux for 5 hours, and then cooled toroom temperature and the solvent was removed by evaporation. The residuewas dissolved in dichloromethane (30 mL) and the organic phase waswashed with water and dried over anhydrous magnesium sulphate, filteredand evaporated. The crude product was recrystallized from isopropanol togive3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine1-oxide, 1.69 g (80%).b)3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine1-oxide (1.27 g, 3 mmol) was taken up in dichloromethane (25 mL). Theyellowish solution was cooled to −78° C. under argon and borontribromide (2.55 mL, 27 mmol) was added dropwise. The red reactionmixture was allowed to warm to room temperature and stirred for 18hours. It was then carefully poured into ice-water (100 mL) and stirredfor 1 hour. The yellow precipitate was filtered off, washed with waterand dried over P₂O₅ under vacuum. The solid was recrystallised fromdichloromethane-ethanol to give3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine1-oxide as a yellow solid, 0.84 g (71%).

EXAMPLE 58

As an example of a compound of the general formula (I) having a1,3,5-triazin-2,4-diyl moiety as central unit,3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine1-oxide was prepared by the following procedure:

a) To a solution of(E)-N-((dimethylamino)methylene)-3,4-dimethoxy-5-nitrobenzamide (1.12 g,4 mmol) ethanol (30 mL) was added3-carbamimidoyl-2-(trifluoromethyl)pyridine 1-oxide (0.82 g, 4 mmol).The reaction mixture was heated to reflux for 5 hours. It was cooled toroom temperature and the solvent was removed by evaporation. The residuewas then dissolved in dichloromethaneisopropanol mixture (50 mL, 70:30)and the organic phase was washed with water, dried over anhydrousmagnesium sulphate, filtered and evaporated. The crude product wasrecrystallized from ethanol to give3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine1-oxide, 1.27 g (75%).b) A portion of3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine 1-oxide (1.269 g, 3 mmol) was taken up in dichloromethane (25mL). The yellowish solution was cooled to −78° C. under argon and borontribromide (2.55 mL, 27 mmol) was added dropwise. The red reactionmixture was allowed to warm to room temperature and stirred for 18 hoursand then carefully poured into ice-water (100 mL) and stirred for 1hour. The yellow precipitate was filtered off, washed with water anddried over P₂O₅ under vacuum. Recrystallisation from adichloromethane-ethanol mixture gave3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazin-2-yl)-2-(trifluoromethyl)pyridine1-oxide as a yellow solid, 1.07 g (90%).

EXAMPLE 59

As an example of a compound of the general formula (I) having apyrrol-2,5-diyl moiety as central unit,5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-2-(2-trifluoromethyl-1-oxypyridin-3-yl)-1H-pyrrole-3-carboxylicacid ethyl ester was prepared by the following procedure:

a) To a stirred solution of methylamine (0.63 mL, 33% EtOH solution, 5mmol) in a mixture of ethanol (25 mL) and acetic acid (0.5 mL) at roomtemperature was added3-oxo-3-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-propionic acid ethylester (1.39 g, 5 mmol). The reaction mixture was heated at reflux fortwo hours whereupon the solvent was removed by evaporation under vacuum.To a solution of the crude product in dimethylformamide (25 mL) wasadded potassium carbonate (2.07 g, 15 mmol) in one portion followed by1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-bromo-ethanone (2.51 g, 5.50mmol) and the mixture was then stirred at 100° C. Once no startingmaterial was detectable by TLC, the reaction mixture was allowed to coolto room temperature and poured onto ice-cold 1 N aqueous hydrochloricacid (100 mL). The resulting precipitate was filtered off, washed withwater and dried. The residue was chromatographed over silica gel.Homogeneous fractions were pooled and evaporated to give5-(3,4-bis-benzyloxy-5-nitro-phenyl)-1-methyl-2-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-1H-pyrrole-3-carboxylicacid ethyl ester, 2.41 g (79%).b) A solution of5-(3,4-bis-benzyloxy-5-nitro-phenyl)-1-methyl-2-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-1H-pyrrole-3-carboxylicacid ethyl ester (0.2 g, 0.30 mmol) in dichloromethane (10 mL) wascooled to −78° C. with stirring and treated under argon with borontribromide (0.30 g, 1.21 mmol). The resulting deep purple suspension wasthen allowed to stir at room temperature for one hour before coolingagain to −78° C. The mixture was quenched by the careful addition ofmethanol. After stirring at room temperature for thirty minutes, thevolatiles were evaporated and the residue stirred with 2 N hydrochloricacid (5 mL) for thirty minutes. The resulting solid was filtered off,washed with water (25 mL) and then cold isopropanol (5 mL) to give5-(3,4-dihydroxy-5-nitro-phenyl)-1-methyl-2-(1-oxy-2-trifluoromethyl-pyridin-3-yl)-1H-pyrrole-3-carboxylicacid ethyl ester as a yellow solid, 0.13 g (93%).

EXAMPLE 60

As an example of a compound of the general formula (I) having a2H-tetrazol-2,5-diyl moiety as central unit,5-[2-(5-trifluoromethyl-1-oxy-pyridin-2-yl)-2H-tetrazol-5-yl]-3-nitrobenzene-1,2-diolwas prepared by the following procedure:

a) A mixture of 3,4-bis-benzyloxy-5-nitro-benzonitrile (0.54 g, 1.50mmol), sodium azide (0.15 g, 2.25 mmol) and ammonium chloride (0.12 g,2.25 mmol) in dimethylformamide (3 mL) was stirred at 85° C. for 20hours. After cooling to room temperature, the reaction mixture waspoured onto water (30 mL) and acidified with dilute hydrochloric acid.The resulting precipitate was collected, washed with water and dried toyield 5-(3,4-bis-benzyloxy-5-nitro-phenyl)-2H-tetrazole, 0.53 g (87%).b) 2-Chloro-5-trifluoromethyl-1-oxy-pyridine (0.20 g, 1.00 mmol) wasadded to a stirred suspension of5-(3,4-bis-benzyloxy-5-nitro-phenyl)-2H-tetrazole (0.4 g, 1.00 mmol) andpotassium carbonate (0.14 g, 1 mmol) in acetonitrile (10 mL). Thereaction mixture was stirred at room temperature till completion, thendiluted with dichloromethane and washed with water. The organic phasewas separated, dried over anhydrous magnesium sulphate, filtered andevaporated to dryness to leave a crude residue that was recrystallisedfrom a dichloromethaneisopropanol mixture to afford2-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-tetrazol-2-yl]-5-trifluoromethyl-1-oxy-pyridine,0.40 g (71%).c) A solution of2-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-tetrazol-2-yl]-5-trifluoromethyl-1-oxy-pyridine(0.282 g, 0.5 mmol) in dichloromethane (15 mL) was cooled to −78° C.with stirring under argon and treated with boron tribromide (1.00 g,4.00 mmol) dropwise. The resulting deep purple suspension was thenallowed to stir at room temperature for one hour before cooling again to−78° C. The mixture was quenched by the careful addition of methanol.After stirring at room temperature for thirty minutes, the volatileswere evaporated and the residue stirred with 2 N hydrochloric acid (5mL) for thirty minutes. The resulting solid was filtered off, washedwith water (25 mL) and then cold isopropanol (5 mL) to give5-[2-(5-trifluoromethyl-1-oxy-pyridin-2-yl)-2H-tetrazol-5-yl]-3-nitrobenzene-1,2-diolas a yellow solid, 0.17 g, (90%).

EXAMPLE 61

As an example of a compound of the general formula (I) having a1,3-thiazol-2,4-diyl moiety as central unit,5-[2-[2-(trifluoromethyl)-1-oxy-pyridin-3-yl]-[1,3]-thiazol-4-yl]-3-nitrobenzene-1,2-diolwas prepared by the following procedure:

a) A mixture of 2-(trifluoromethyl)-1-oxy-pyridine-3-carbothioamide(0.24 g, 1.10 mmol) and1-[3,4-bis(benzyloxy)-5-nitrophenyl]-2-bromoethanone (0.50 g, 1.10 mmol)were refluxed overnight in absolute ethanol (5 mL). After cooling toroom temperature, the reaction mixture was poured onto water (50 mL).The resulting precipitate was filtered off, washed with water (25 mL)and dried. Recrystallisation from dichloromethaneisopropanol afforded3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,3]-thiazol-2-yl]-2-trifluoromethyl-1-oxy-pyridine,0.55 g (87%).b) A solution of3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,3]-thiazol-2-yl]-2-trifluoromethyl-1-oxy-pyridine(0.15 g, 0.26 mmol), in dichloromethane (10 mL) was cooled to −78° C.and treated under argon, with boron tribromide (0.26 g, 1.03 mmol). Theresulting deep purple suspension was then allowed to stir at roomtemperature for one hour before cooling again to −78° C. The mixture wasquenched by careful addition of methanol. After stirring at roomtemperature for thirty minutes, the volatiles were evaporated and theresidue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes.The resulting solid was filtered off, washed with water (25 mL) and thencold isopropanol (5 mL) to give5-[2-[2-(trifluoromethyl)-1-oxy-pyridin-3-yl]-[1,3]-thiazol-4-yl]-3-nitrobenzene-1,2-diolas a yellow solid, 0.09 g (87%).

EXAMPLE 62

As an example of a compound of the general formula (I) having a1,2,4-triazol-3,5-diyl moiety as central unit,5-[4-methyl-5-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-3-nitro-benzene-1,2-diolwas prepared by the following procedure:

a) To a stirred solution of 3,4-dimethoxy-5-nitro-benzoyl chloride (0.50g, 2.04 mmol) in dichloromethane (10 mL) at 0° C., was added dropwisemethylamine (1.02 mL, 2.04 mmol, 2 M in THF). The reaction mixture wasstirred at room temperature till all starting material disappeared, thendiluted with dichloromethane and washed with water. The organic phasewas dried over anhydrous magnesium sulphate, filtered and evaporated todryness to leave a crude residue that was recrystallised from adichloromethaneisopropanol mixture to afford3,4-dimethoxy-N-methyl-5-nitro-benzamide, 0.44 g (89%).b) To a stirred suspension of 3,4-dimethoxy-N-methyl-5-nitro-benzamide(0.40 g, 1.66 mmol) in toluene (10 mL) was added phosphorouspentachloride (0.38 g, 1.83 mmol) portionwise. Upon completion ofaddition, the reaction mixture was warmed to reflux till completedisappearance of starting material. Evaporation to dryness resulted in acrude solid that was washed with diethyl ether, affording3,4-dimethoxy-N-methyl-5-nitro-benzimidoyl chloride, 0.37 g (85%).c) A mixture of 2-trifluoromethyl-1-oxy-3-pyridinecarbonitrile (0.47 g,2.50 mmol), sodium azide (0.24 g, 3.75 mmol) and ammonium chloride (0.20g, 3.75 mmol) in dimethylformamide (2.5 mL) was stirred at 85° C. for 20hours. After cooling to room temperature, the reaction mixture waspoured onto water (20 mL) and acidified with dilute hydrochloric acid.The resulting precipitate was collected, washed with water and dried toyield 3-(2H-tetrazol-5-yl)-2-trifluoromethyl-1-oxy-pyridine, 0.52 g(90%).d) 3,4-Dimethoxy-N-methyl-5-nitro-benzimidoyl chloride (0.26 g, 1.08mmol) was added to a stirred solution of3-(2H-tetrazol-5-yl)-2-trifluoromethyl-1-oxy-pyridine (0.23 g, 1 mmol)in dry pyridine (3 mL), preheated to 50° C. The resulting mixture wascautiously heated to 75-90° C. and maintained at this temperature untilnitrogen evolution ceased. The mixture was then poured onto water (30mL) and extracted with dichloromethane (25 mL). The organic phase wasseparated, dried over anhydrous magnesium sulphate, filtered andevaporated to dryness. The resulting residue was purified bychromatography to afford3-[5-(3,4-dimethoxy-5-nitro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-2-trifluoromethyl-1-oxy-pyridine,0.25 g (59%).e) To a stirred suspension of3-[5-(3,4-dimethoxy-5-nitro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-2-trifluoromethyl-1-oxy-pyridine(0.20 g, 0.47 mmol) in dichloromethane (20 mL) at −78° C. under argonwas added boron tribromide (0.47 g, 1.88 mmol) dropwise. The resultingpurple suspension was then allowed to stir at room temperature for sevenhours before being cooled in an ice-water bath. The mixture wascarefully quenched by the addition of methanol. After stirring at roomtemperature for thirty minutes, the volatiles were evaporated and theresidue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes.The resulting solid was filtered off, washed with water (25 mL) and thencold isopropanol (5 mL) to give, after drying,5-[4-Methyl-5-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-3-nitro-benzene-1,2-diolwas obtained as an orange solid, 0.16 g (86%).

EXAMPLE 63

As an example of a compound of the general formula (I) having a1,2,3-thiadiazol-4,5-diyl moiety as central unit,5-[5-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-[1,2,3]thiadiazol-4-yl]-3-nitrobenzene-1,2-diolwas prepared by the following procedure:

a) A mixture of1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-ethanone(0.50 g, 0.93 mmol), ethyl carbazate (0.11 g, 1.06 mmol) andp-toluenesulfonic acid (4 mg) in toluene (10 mL) was refluxed untilazeotropic distillation of water ceased. The reaction mixture was cooledto room temperature, the solvents were evaporated to dryness, and thecrude solid was triturated with diethyl ether (15 mL), filtered anddried yieldingN′-[1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-ethylidene]-hydrazinecarboxylicacid ethyl ester, 0.49 g (84%).b) A mixture ofN′-[1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-ethylidene]-hydrazinecarboxylicacid ethyl ester (0.40 g, 0.64 mmol), in thionyl chloride (2 mL) wasrefluxed until no more starting material was detected by TLC. Excess ofsolvent was removed and the residue was purified by chromatography oversilica gel using a mixture of dichloromethane/ethanol as eluent.Homogeneous fractions were pooled and evaporated to afford3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,3]thiadiazol-5-yl]-2-trifluoromethyl-1-oxy-pyridine,0.19 g (51%).c) A solution of3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,3]thiadiazol-5-yl]-2-trifluoromethyl-1-oxy-pyridine(0.15 g, 0.26 mmol) in dichloromethane (10 mL) was cooled to −78° C.with stirring and treated under argon with boron tribromide (0.26 g,1.03 mmol). The resulting deep purple suspension was then allowed tostir at room temperature for one hour before cooling again to −40° C.The mixture was quenched by the careful addition of methanol. Afterstirring at room temperature for thirty minutes, the volatiles wereevaporated and the residue stirred with 2 N hydrochloric acid (5 mL) forthirty minutes. The resulting solid was filtered off, washed with water(25 mL) and then cold isopropanol (5 mL) to give5-[5-(2-trifluoromethyl-1-oxy-pyridin-3-yl)-[1,2,3]thiadiazol-4-yl]-3-nitrobenzene-1,2-diolas a yellow solid, 0.09 g (89%).

EXAMPLE 64

As an example of a compound of the general formula (I) having a1,2,4-oxadiazol-3,5-diyl moiety as central unit,5-[5-[2-(trifluoromethyl)-1-oxypyridin-3-yl]-[1,2,4]-oxadiazol-3-yl]-3-nitrobenzene-1,2-diolwas prepared by the following procedure:

a) To a stirred solution of 2-trifluoromethyl nicotinic acid (0.38 g, 2mmol) in dimethylformamide (10 mL) at room temperature was added1,1-carbonyldiimidazole (0.34 g, 2.10 mmol) in one portion. Theresulting yellow mixture was allowed to stir for ninety minuteswhereupon 3,4-bis(benzyloxy)-N′-hydroxy-5-nitrobenzamidine (0.79 g, 2mmol) was added in one portion. The resulting mixture was stirred atroom temperature for two hours and then poured onto water (100 mL). Theresulting precipitate was filtered off, washed with water and dried.After recrystallisation from dichloromethaneisopropanol3,4-bis(benzyloxy)-5-nitro-N-(2-(trifluoromethyl)nicotinoyloxy)benzimidamidewas obtained, as a light yellow solid, 0.88 g (78%).b) To a stirred solution of the solid obtained above (0.26 g, 0.46 mmol)in tetrahydrofuran (15 mL) at room temperature under argon was added a 1N solution of tetrabutylammonium fluoride in tetrahydrofuran (0.7 mL,0.7 mmol). The resulting clear yellow solution was allowed to stir atroom temperature for four hours. Additional tetrabutylammonium fluoride(0.7 mmol) was added and the reaction mixture was allowed to stir forfifteen hours at room temperature and then ten hours at 55° C. Aftercooling to room temperature, the reaction mixture was poured onto water(150 mL). The resulting precipitate was filtered off, washed with waterand dried. The crude product was chromatographed over silica gel usingdichloromethane as eluent. Homogeneous fractions were pooled andevaporated to afford3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)pyridineas an off-white solid, 0.21 g (82%).c) To a stirred solution of3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)pyridine(0.33 g, 0.60 mmol) in dichloromethane (6 mL) at 0° C. was added ureahydrogen peroxide complex (0.28 g, 3 mmol) and trifluoroacetic anhydride(0.43 mL, 3.00 mmol). After the reaction mixture had been stirred atroom temperature for 60 hours, solid residues were filtered off. Theorganic phase was then successively treated with an aqueous solution ofNa₂S₂O₅ (0.6 g, 3.45 mmol, dissolved in 20 mL of water), 0.4 Nhydrochloric acid (20 mL), a saturated solution of NaHCO₃ (20 mL), water(20 mL) and brine (20 mL). The organic phase was dried over anhydrousmagnesium sulphate, filtered and evaporated to dryness. The residue waschromatographed over silica gel using dichloromethane/ethanol as eluent.Homogeneous fractions were pooled and evaporated, and the residue wasrecrystallised from dichloromethaneisopropanol to afford3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)-1-oxy-pyridineas a yellow solid, 0.23 g (68%).d) A solution of3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)-1-oxy-pyridine(0.10 g, 0.18 mmol) in dichloromethane (5 mL) was cooled to −78° C. withstirring under argon and treated with boron tribromide (0.18 g, 0.74mmol) dropwise. The resulting deep purple suspension was then allowed tostir at room temperature for one hour before cooling again to −78° C.The mixture was quenched by the careful addition of methanol. Afterstirring at room temperature for thirty minutes, the volatiles wereevaporated and the residue stirred with 2 N hydrochloric acid (5 mL) forthirty minutes. The resulting solid was filtered off, washed with water(25 mL) and then cold isopropanol (5 mL) to give5-[5-[2-(trifluoromethyl)-1-oxypyridin-3-yl]-[1,2,4]-oxadiazol-3-yl]-3-nitrobenzene-1,2-diolas a yellow solid, 0.06 g (88%).

The invention claimed is:
 1. A method of increasing the amount of orallyadministered L-DOPA which reaches the brain of a patient afflicted byParkinson's disease and thereby treating Parkinson's disease whichcomprises administering orally to said patient a COMT-inhibitoryeffective amount of a compound of the Formula (I):

wherein R₁ and R₂ are independently from each other hydrogen, optionallysubstituted lower alkanoyl or aroyl; X represents a methylene group; Yrepresents an atom of oxygen NH, or sulphur; n represents the number 0,1, 2 or 3 and m represents the number 0 or 1; R₃ represents a pyridineN-oxide group according to the formula A, B or C, which is connected asindicated by the unmarked bond:

where R₄, R₅, R₆ and R₇ independently from each other representhydrogen, C₁-C₆-alkyl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy, C₆-C₁₂-aryloxy ora C₆-C₁₂-thioaryl group, C₁-C₆-alkanoyl or C₇-C₁₃-aroyl group, amino,C₁-C₆-alkylamino, C₁-C₆-dialkylamino, C₃-C₁₂-cycloalkylamino orC₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl orC₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano,nitro or a heteroaryl group; or where two or more of residues R₄, R₅, R₆and R₇ taken together represent aliphatic or heteroaliphatic rings oraromatic or heteroaromatic rings and wherein P represents a central unitselected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl and1,2,4-oxadiazol-3,5-diyl, wherein the regioisomers of the central unitinclude both regioisomers realizable by exchange of the nitrocatecholmoiety and the —(X)_(n)—(Y)_(m)—R₃ moiety.
 2. A method as claimed inclaim 1, wherein the compound of Formula (I) is5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.3. A method of inhibiting COMT in the periphery which comprises theadministration to a patient in need thereof a COMT-inhibitory amount ofa compound of the Formula (I):

wherein R₁ and R₂ are independently from each other hydrogen, optionallysubstituted lower alkanoyl or aroyl; X represents a methylene group; Yrepresents an atom of oxygen NH, or sulphur; n represents the number 0,1, 2 or 3 and m represents the number 0 or 1; R₃ represents a pyridineN-oxide group according to the formula A, B or C, which is connected asindicated by the unmarked bond:

where R₄, R₅, R₆ and R₇ independently from each other representhydrogen, C₁-C₆-alkyl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy, C₆-C₁₂-aryloxy ora C₆-C₁₂-thioaryl group, C₁-C₆-alkanoyl or C₇-C₁₃-aroyl group, amino,C₁-C₆-alkylamino, C₁-C₆-dialkylamino, C₃-C₁₂-cycloalkylamino orC₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl orC₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano,nitro or a heteroaryl group; or where two or more of residues R₄, R₅, R₆and R₇ taken together represent aliphatic or heteroaliphatic rings oraromatic or heteroaromatic rings and wherein P represents a central unitselected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl and1,2,4-oxadiazol-3,5-diyl, wherein the regioisomers of the central unitinclude both regioisomers realizable by exchange of the nitrocatecholmoiety and the —(X)_(n)—(Y)_(m)—R₃ moiety.
 4. A method as claimed inclaim 3, wherein the compound of Formula (I) is5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.5. A method of manufacture of a pharmaceutical composition suitable forthe treatment of Parkinson's disease which comprises formulating acompound of the Formula (I):

wherein R₁ and R₂ are independently from each other hydrogen, optionallysubstituted lower alkanoyl or aroyl; X represents a methylene group; Yrepresents an atom of oxygen NH, or sulphur; n represents the number 0,1, 2 or 3 and m represents the number 0 or 1; R₃ represents a pyridineN-oxide group according to the formula A, B or C, which is connected asindicated by the unmarked bond:

where R₄, R₅, R₆ and R₇ independently from each other representhydrogen, C₁-C₆-alkyl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy, C₆-C₁₂-aryloxy ora C₆-C₁₂-thioaryl group, C₁-C₆-alkanoyl or C₇-C₁₃-aroyl group, amino,C₁-C₆-alkylamino, C₁-C₆-dialkylamino, C₃-C₁₂-cycloalkylamino orC₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl orC₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano,nitro or a heteroaryl group; or where two or more of residues R₄, R₅, R₆and R₇ taken together represent aliphatic or heteroaliphatic rings oraromatic or heteroaromatic rings and wherein P represents a central unitselected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl and1,2,4-oxadiazol-3,5-diyl, wherein the regioisomers of the central unitinclude both regioisomers realizable by exchange of the nitrocatecholmoiety and the —(X)_(n)—(Y)_(m)—R₃ moiety and a pharmaceuticallyacceptable carrier therefore.
 6. A method as claimed in claim 5, whereinthe compound of the Formula (I) is5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.7. A method of reducing O-methylation of L-DOPA in a patient sufferingfrom Parkinson's disease treated with L-DOPA which comprises theadministration of a compound of the Formula (I):

wherein R₁ and R₂ are independently from each other hydrogen, optionallysubstituted lower alkanoyl or aroyl; X represents a methylene group; Yrepresents an atom of oxygen NH, or sulphur; n represents the number 0,1, 2 or 3 and m represents the number 0 or 1; R₃ represents a pyridineN-oxide group according to the formula A, B or C, which is connected asindicated by the unmarked bond:

where R₄, R₅, R₆ and R₇ independently from each other representhydrogen, C₁-C₆-alkyl, C₁-C₆-thioalkyl, C₁-C₆-alkoxy, C₆-C₁₂-aryloxy ora C₆-C₁₂-thioaryl group, C₁-C₆-alkanoyl or C₇-C₁₃-aroyl group, amino,C₁-C₆-alkylamino, C₁-C₆-dialkylamino, C₃-C₁₂-cycloalkylamino orC₃-C₁₂-heterocycloalkylamino, C₁-C₆-alkylsulphonyl orC₆-C₁₂-arylsulphonyl, halogen, C₁-C₆-haloalkyl, trifluoromethyl, cyano,nitro or a heteroaryl group; or where two or more of residues R₄, R₅, R₆and R₇ taken together represent aliphatic or heteroaliphatic rings oraromatic or heteroaromatic rings and wherein P represents a central unitselected from the regioisomers of 1,3,4-oxadiazol-2,5-diyl and1,2,4-oxadiazol-3,5-diyl, wherein the regioisomers of the central unitinclude both regioisomers realizable by exchange of the nitrocatecholmoiety and the —(X)_(n)—(Y)_(m)—R₃ moiety.
 8. A method as claimed inclaim 7, wherein the compound of the Formula (I) is5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol.